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RIPK1

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a ubiquitously expressed 76 kDa protein kinase that serves as a central regulator of programmed cell death pathways, including apoptosis and necroptosis, while also mediating inflammatory responses through NF-κB signaling.^[1]^[2] Originally identified in 1995 as a death domain-containing protein that interacts with Fas/APO-1 (CD95), RIPK1 was characterized for its ability to induce cell death in yeast two-hybrid screens.^[2] Structurally, RIPK1 comprises an N-terminal kinase domain responsible for its enzymatic activity, an intermediate RIP homotypic interaction motif (RHIM) that enables oligomerization with other RHIM-containing proteins, and a C-terminal death domain (DD) that facilitates binding to death receptors and adaptor proteins such as TRADD and FADD.^[1]^[2] In its scaffold role, RIPK1 assembles signaling complexes at tumor necrosis factor receptor 1 (TNFR1) to promote ubiquitination-dependent activation of NF-κB and MAPK pathways, thereby driving expression of pro-survival and pro-inflammatory genes like TNF-α and IL-6.^[1]^[2] However, under conditions of caspase inhibition or viral infection, RIPK1's kinase activity phosphorylates RIPK3, leading to the formation of the necrosome complex with MLKL, which executes necroptosis—a lytic form of cell death that amplifies inflammation.^[2]^[1] RIPK1 also modulates apoptosis by recruiting caspase-8 to the complex I or IIb, and its activity is tightly regulated by post-translational modifications such as ubiquitination by cIAP1/2 and phosphorylation by IKK and MK2 to balance survival and death.^[2] Genetic studies reveal that RIPK1 deficiency leads to perinatal lethality in mice, with death occurring shortly after birth due to unchecked inflammation and cell death, while human biallelic loss-of-function mutations cause early-onset inflammatory bowel disease and immunodeficiency.^[2]^[1] Given its dual roles, pharmacological inhibition of RIPK1 kinase activity with selective inhibitors like GSK2982772 and DNL747 has shown promise in preclinical models and has been tested in clinical trials for conditions including amyotrophic lateral sclerosis, Alzheimer's disease, psoriasis, and ulcerative colitis, though with mixed results. As of 2025, the therapeutic potential of RIPK1 inhibition continues to be explored in preclinical and early clinical studies for these diseases.^[1]^[3]^[4]

Molecular Structure and Regulation

Protein Domains and Architecture

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a 676-amino acid protein that functions as a serine/threonine kinase, organized into three principal domains: an N-terminal kinase domain spanning residues 1-330, an intermediate domain encompassing residues 331-550 that includes the receptor-interacting protein (RIP) homotypic interaction motif (RHIM), and a C-terminal death domain covering residues 551-676.^[5]^[6] This modular architecture enables RIPK1 to integrate diverse signaling inputs, with the kinase domain driving catalytic activity, the intermediate domain supporting oligomerization, and the death domain facilitating complex assembly.^[7] The N-terminal kinase domain adopts the canonical bilobal fold characteristic of protein kinases, comprising a smaller N-lobe rich in β-sheets for ATP binding and a larger C-lobe dominated by α-helices that positions substrates for phosphorylation. The ATP-binding cleft lies between these lobes, while the activation loop (residues Asp156-Glu196) regulates access to the active site; notably, Asp156 serves as the catalytic base essential for abstracting a proton during phosphotransfer.^[8] Crystal structures of the human RIPK1 kinase domain, often in complex with inhibitors, confirm this conserved architecture and highlight allosteric sites that modulate activity without disrupting the core fold.^[9] Within the intermediate domain, the RHIM motif (approximately residues 496-583 in humans) forms an amyloid-like β-strand structure that promotes self-association and interactions with RHIM domains in proteins like RIPK3 and ZBP1. This motif enables the formation of higher-order oligomers, such as fibrils, through parallel β-sheet stacking of conserved IQIG sequence segments. A 2024 cryo-electron microscopy structure of the mouse RIPK1 RHIM domain (residues 485-566) demonstrated its organization as a symmetric homo-tetramer, with each subunit contributing two β-strands to a protofilament core stabilized by hydrophobic and hydrogen-bonding interactions.^[10]^[11] The C-terminal death domain is a Type I death domain, featuring a compact six-α-helical bundle topology that mediates homotypic interactions with other death domains in signaling adaptors like TRADD and FADD. This structure positions conserved charged residues on one face for electrostatic-driven assembly into oligomeric complexes, essential for propagating death receptor signals.^[10]^[12] The domain organization of RIPK1 exhibits high evolutionary conservation across mammalian species, with sequence identity exceeding 80% in the kinase and death domains between humans and rodents, underscoring its preserved role in innate immune regulation.^[13]^[14] This topological stability facilitates comparable scaffolding and kinase functions in diverse mammalian lineages.

Post-Translational Modifications

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) undergoes extensive phosphorylation, which critically regulates its kinase activity and signaling outcomes. Autophosphorylation at Ser-166 within the activation loop of the kinase domain is a pivotal event that enhances RIPK1's catalytic function, particularly in promoting necroptosis and apoptosis upon TNF receptor stimulation.^[15] Additional phosphorylation at Thr-189 (Thr-190 in mice), mediated by TBK1, inhibits Ser-166 autophosphorylation and thereby suppresses RIPK1 activation, favoring cell survival.^[16] Upstream kinases such as TAK1 phosphorylate RIPK1 at sites like Ser-321 to prevent its association with death complexes, while IKKβ targets inhibitory residues (e.g., Ser-25, Ser-320) to block kinase-dependent cell death and promote NF-κB-mediated anti-apoptotic responses. Recent investigations, including 2023 studies on AMPK-mediated phosphorylation at Ser-416, underscore how these modifications fine-tune RIPK1's role in metabolic and inflammatory regulation, with dephosphorylation by protein phosphatase 1 gamma (PP1γ) enabling RIPK1 hyperactivation in chronic inflammation.^[17]^[18] Ubiquitination represents another major regulatory layer for RIPK1, influencing its stability, localization, and interactions. K63-linked ubiquitination at Lys-377 (Lys-376 in mice), facilitated by the linear ubiquitin chain assembly complex (LUBAC) in coordination with cIAP1/2, conjugates ubiquitin chains that recruit NEMO and TAB2/3 to the TNFR1 complex, thereby driving NF-κB activation and pro-survival signaling.^[19] This modification stabilizes RIPK1 in its scaffold configuration, preventing lethal kinase activity. In contrast, K48-linked ubiquitination marks RIPK1 for proteasomal degradation, though this pathway is less dominant and primarily activated under conditions of excessive signaling to attenuate responses.^[16] Deubiquitinases like CYLD and A20 counteract these chains, with CYLD removing K63 linkages to shift RIPK1 toward death induction.^[20] Beyond phosphorylation and ubiquitination, RIPK1 is subject to proteolytic cleavage and emerging non-canonical modifications. Caspase-8 cleaves RIPK1 at Asp-324 (Asp-325 in mice) within the intermediate domain, generating a C-terminal fragment that disrupts RIPK3 recruitment and thereby restricts necroptosis while facilitating apoptosis during TNF-induced signaling.^[21] Mutations at this site, as observed in caspase-8 cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome, lead to unchecked necroptosis and inflammation.^[22] Less characterized modifications, such as methylation and acetylation, are gaining attention; 2025 studies reveal that RIPK1 senses S-adenosylmethionine (SAM) scarcity—a key methyl donor—leading to its activation and cell death, suggesting potential SAM-dependent methylation events that integrate metabolism with signaling.^[23] Acetylation impacts remain underexplored but may influence RIPK1's inflammatory outputs in disease contexts.^[7] The interplay of these post-translational modifications orchestrates RIPK1's dual roles as a scaffold or kinase. In the scaffold mode, K63 ubiquitination and inhibitory phosphorylations (e.g., by IKKβ and TAK1) anchor RIPK1 to complex I at TNFR1, enabling NF-κB and MAPK activation for survival and inflammation control.^[20] Conversely, deubiquitination, caspase cleavage, and dephosphorylation (e.g., removal of Ser-166 inhibition) liberate RIPK1 for kinase-dependent assembly of complex II, driving apoptosis or necroptosis when survival signals fail.^[17] This dynamic balance ensures RIPK1 acts as a checkpoint, with dysregulation implicated in inflammatory pathologies.^[24]

Biological Functions

Promotion of Cell Survival

RIPK1 plays a pivotal role in promoting cell survival through its involvement in tumor necrosis factor (TNF) receptor signaling, where it acts as a scaffold protein that facilitates the activation of pro-survival pathways. Upon TNF binding to TNFR1, RIPK1 is recruited to the receptor complex and undergoes K63-linked ubiquitination by cellular inhibitors of apoptosis (cIAPs), which serves as a platform for the recruitment of the NF-κB essential modifier (NEMO) and the IκB kinase (IKK) complex.^[25] This ubiquitination-dependent interaction enables IKK activation, leading to the phosphorylation and degradation of IκB, thereby allowing NF-κB translocation to the nucleus and transcription of anti-apoptotic genes such as c-FLIP and Bcl-2.^[26] Consequently, this pathway inhibits caspase-8-mediated apoptosis and supports cellular viability in response to TNF stimulation.^[27] In the context of genotoxic stress, such as that induced by DNA-damaging agents like chemotherapy or radiation, RIPK1 contributes to survival signaling by participating in an ATM-NEMO complex that drives NF-κB activation. ATM kinase, activated by DNA double-strand breaks, phosphorylates NEMO, promoting its translocation to the cytoplasm where it associates with RIPK1 to recruit TAK1 and the IKK complex, ultimately inducing NF-κB-dependent expression of genes involved in DNA repair and anti-apoptotic responses.^[28] Additionally, RIPK1 facilitates the activation of stress-responsive MAPKs, including p38 and JNK, through TAK1-mediated signaling, which enhances cellular adaptation to genotoxic insults by promoting DNA damage repair mechanisms and inhibiting pro-death pathways.^[29] This kinase-dependent and scaffold-mediated coordination underscores RIPK1's role in maintaining genomic integrity and cell survival under oxidative or radiation-induced stress.^[30] Beyond TNF and genotoxic responses, RIPK1 supports survival in innate immune signaling pathways, particularly through Toll-like receptors (TLRs) 3 and 4. In TLR3/4 activation by viral or bacterial ligands, RIPK1 interacts with the adaptor protein TRIF to propagate signals leading to type I interferon (IFN) production via IRF3 activation, which bolsters antiviral defenses and cellular resilience.^[2] These mechanisms collectively enhance immune-mediated cell protection without triggering death pathways. A key aspect of RIPK1's pro-survival function is its kinase-independent scaffold activity, which persists even when kinase inhibition occurs, such as with necrostatin-1 (Nec-1). Kinase-dead RIPK1 mutants or Nec-1-treated cells retain the ability to assemble signaling complexes at TNFR1 or other receptors, recruiting TRAFs and IKK to sustain NF-κB and MAPK activation, thereby preventing apoptosis and supporting long-term viability.^[31] This scaffold role highlights RIPK1's versatility in integrating survival signals across diverse stimuli, independent of its catalytic activity.^[30]

Induction of Cell Death Pathways

RIPK1 plays a pivotal role in the induction of programmed cell death pathways, particularly when survival signals are compromised, such as during tumor necrosis factor (TNF) stimulation in the absence of sufficient NF-κB activation. In these contexts, RIPK1 shifts from a scaffold promoting survival to a kinase that drives necroptosis, apoptosis, or integrated forms like PANoptosis, depending on the cellular environment and regulatory modifications.^[26] This context-dependent activation underscores RIPK1's function as a central hub in death signaling complexes.^[32] In necroptosis, RIPK1 kinase activity is triggered upon TNF receptor 1 (TNFR1) engagement when caspase-8 is inhibited, leading to autophosphorylation at Ser-166, which enhances its kinase function and facilitates recruitment of RIPK3 through RIP homotypic interaction motif (RHIM) interactions.^[32] The RIPK1-RIPK3 complex, known as the necrosome, then phosphorylates mixed lineage kinase domain-like (MLKL), promoting MLKL oligomerization and translocation to the plasma membrane to form pores that cause lytic cell death.^[33] This pathway is tightly regulated, as RIPK1's kinase-independent scaffolding can initially suppress necroptosis until deubiquitination or other signals tip the balance toward execution.^[26] For apoptosis, RIPK1 contributes to the extrinsic pathway by transitioning from complex I (a prosurvival TNFR1-associated structure) to complex II upon deubiquitination, where it recruits Fas-associated death domain (FADD) and pro-caspase-8 to form the ripoptosome.^[33] Caspase-8 then cleaves RIPK1 at specific sites, releasing fragments that amplify caspase activation and effector caspase-3/7-mediated apoptotic execution, while preventing crossover to necroptosis.^[34] This cleavage is essential for efficient apoptosis in type II cells, where mitochondrial amplification is limited.^[35] RIPK1 also serves as a central switch in PANoptosis, an inflammatory cell death integrating pyroptosis, apoptosis, and necroptosis, often triggered by innate immune sensors like ZBP1.^[36] In PANoptosomes, RIPK1 interacts with ZBP1 via RHIM domains, enhancing kinase activity and recruiting inflammasome components such as NLRP3 and ASC, alongside caspase-1/8 and RIPK3-MLKL, to coordinately drive gasdermin-mediated pyroptosis, caspase-dependent apoptosis, and MLKL-driven necroptosis.^[37] Recent studies highlight ZBP1-RIPK1 interactions as critical amplifiers in viral and sterile inflammation contexts, with 2025 research emphasizing their role in skin tissues like keratinocytes.^[38] Key regulatory checkpoints govern RIPK1's pro-death functions, particularly deubiquitination by CYLD or A20, which removes K63-linked ubiquitin chains from RIPK1, destabilizing complex I and promoting its dissociation to enable death complex assembly.^[26] CYLD-mediated deubiquitination specifically enhances RIPK1's transition to necroptosis or apoptosis by facilitating RHIM-dependent interactions, while A20's dual ubiquitin-editing activity fine-tunes this shift to prevent excessive inflammation.^[39] These modifications act as molecular rheostats, determining whether RIPK1 drives survival or death based on ubiquitin landscape alterations.^[40]

Role in Diseases

Neurodegenerative Disorders

In Alzheimer's disease (AD), hyperactivation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in microglia drives neuroinflammation and exacerbates disease pathology. RIPK1 is highly expressed in microglia within human AD brains and in amyloid precursor protein (APP)/presenilin 1 (PS1) mouse models, where it mediates a disease-associated microglial (DAM) response by promoting transcription of genes such as Cst7 (encoding cystatin F) and CH25H. This leads to lysosomal dysfunction, impaired amyloid-β (Aβ) phagocytosis, and accumulation of amyloid plaques, alongside elevated production of proinflammatory cytokines like tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Pharmacological inhibition of RIPK1 kinase activity with necrostatin-1s (Nec-1s) or genetic knockdown reduces plaque burden, cytokine levels, and cognitive deficits in these models, highlighting its role in sustaining a maladaptive microglial state.^[41] Aβ oligomers further contribute to neuronal loss in AD by inducing RIPK1-mixed lineage kinase domain-like (MLKL)-dependent necroptosis. Aβ oligomers stimulate microglia to release TNF-α, which activates the RIPK1-RIPK3-MLKL pathway in neurons, resulting in MLKL phosphorylation and membrane permeabilization; this process is corroborated by elevated phosphorylated MLKL (pMLKL) in postmortem AD hippocampal neurons and correlation with Aβ burden. In mouse models, intracerebroventricular injection of Aβ oligomers causes neurodegeneration and memory impairment, effects attenuated by MLKL knockout or RIPK3 inhibition with GSK'872, underscoring microglia-neuron crosstalk in propagating necroptotic damage. As of 2025, phase I clinical trials of brain-penetrant RIPK1 inhibitors, such as SIR9900, have demonstrated safety, dose-proportional pharmacokinetics, and approximately 90% peripheral target engagement in healthy and elderly participants, with cerebrospinal fluid penetration supporting potential efficacy in AD.^[42]^[43] In amyotrophic lateral sclerosis (ALS), RIPK1 promotes motor neuron death primarily through necroptosis, acting in a non-cell-autonomous manner via glial interactions. Human induced pluripotent stem cell-derived motor neurons cocultured with astrocytes from sporadic ALS patients undergo selective death mediated by RIPK1 and MLKL, independent of caspases, as evidenced by rescue with RIPK1 inhibitors like Nec-1; similar necroptotic mechanisms occur in familial ALS models. Mutations in superoxide dismutase 1 (SOD1), such as in SOD1^G93A transgenic mice, enhance RIPK1 signaling by amplifying inflammation and necroptosis in motor neurons and oligodendrocytes, leading to axonal degeneration observed in both murine tissues and human ALS samples. However, the phase 2 trial of the brain-penetrant RIPK1 inhibitor SAR443820 in ALS failed to meet its primary endpoint and was terminated as of 2024.^[44]^[45]^[3] RIPK1 also contributes to oligodendrocyte death and demyelination in multiple sclerosis (MS). In MS cortical lesions, defective caspase-8 processing shifts cell death toward necroptosis, with insoluble RIPK1/RIPK3 aggregates and pMLKL detected in oligodendrocytes, correlating with disease severity. TNF-α, abundant in MS lesions, directly induces RIPK1-dependent necroptosis in oligodendrocytes in vitro, an effect blocked by the RIPK1 inhibitor 7-Cl-O-Nec-1 (7N-1). In animal models like cuprizone-induced demyelination and experimental autoimmune encephalomyelitis (EAE), TNF-driven necroptosis exacerbates oligodendrocyte loss and myelin damage, while RIPK1 or RIPK3 inhibition with 7N-1 or genetic knockout preserves myelin integrity and reduces inflammation.^[46] Common mechanisms across these neurodegenerative disorders position RIPK1 as a central therapeutic target, where its kinase activity bridges necroptosis, apoptosis, and NF-κB-mediated neuroinflammation to drive neuronal and glial loss. Preclinical studies demonstrate that selective RIPK1 inhibitors mitigate pathology in AD, ALS, and MS models by preserving cell survival and dampening cytokine storms, with phase I/II trials confirming tolerability and brain penetration for select compounds like SAR443820 (DNL788), though others such as DNL747 were discontinued due to toxicity. Human genetic evidence links RIPK1 dysregulation to disease risk, including interactions with ALS-associated variants in TBK1 and OPTN that impair autophagy and enhance RIPK1 activation, as well as elevated RIPK1 expression in AD and MS tissues correlating with progression.^[47]^[48]^[49]

Inflammatory and Autoimmune Conditions

RIPK1 plays a central role in autoinflammatory and autoimmune diseases by dysregulating inflammatory signaling and necroptotic cell death, often through its kinase-dependent activation of pathways like NF-κB and MAPK that amplify cytokine production.^[50] In these conditions, loss-of-function mutations in RIPK1 impair its scaffolding function, leading to unchecked necroptosis in epithelial and immune cells, while hyperactivation exacerbates sterile inflammation.^[51] Pharmacological inhibition of RIPK1 kinase activity has shown promise in preclinical models by reducing tissue damage and cytokine storms without compromising essential survival signals.^[52] In autoinflammatory diseases such as very early-onset inflammatory bowel disease (VEOIBD), biallelic loss-of-function mutations in RIPK1 cause severe intestinal inflammation starting in infancy, characterized by enhanced necroptosis in the intestinal epithelium due to deficient NF-κB-mediated survival signaling.^[53] Patients with these mutations, including partial deletions or homozygous variants, present with malnutrition, recurrent infections, polyarthritis, and fistulizing enterocolitis, often requiring hematopoietic stem cell transplantation for management.^[54] For instance, a homozygous RIPK1 deletion has been linked to lymphopenia and early-onset IBD through impaired epithelial barrier integrity and excessive cell death.^[51] Neonatal cases with biallelic variants exhibit symptoms within the first nine months, highlighting RIPK1's critical role in innate immune homeostasis.^[55] In autoimmune disorders like rheumatoid arthritis (RA), RIPK1-mediated necroptosis contributes to synovial inflammation by promoting the release of damage-associated molecular patterns (DAMPs) from dying fibroblasts and macrophages, perpetuating joint destruction.^[56] Elevated levels of necroptotic markers, including phosphorylated RIPK1, RIPK3, and MLKL, are observed in RA synovial tissues, correlating with disease severity and cytokine production.^[57] Inhibition of RIPK1 kinase activity with compounds like KW2449 ameliorates collagen-induced arthritis in mice by suppressing necroptosis and osteoclastogenesis, reducing paw swelling and inflammatory infiltrates.^[58] Similarly, in systemic lupus erythematosus (SLE), dysregulated RIPK1 signaling heightens TNF sensitivity, leading to excessive apoptosis and inflammation in immune cells, with preclinical models showing that RIPK1 inhibitors protect against lupus nephritis by limiting podocyte and endothelial necroptosis.^[59] Recent studies indicate reduced RIPK1 adapter protein levels in SLE patients, potentially exacerbating TNF-driven responses, though specific polymorphisms remain under investigation.^[60] During sepsis and septic shock, RIPK1 kinase activity drives endothelial and immune cell necroptosis, amplifying the cytokine storm through sustained TNF and IL-1β release, which worsens multi-organ failure.^[61] In TNF/zVAD-induced shock models, genetic or pharmacological RIPK1 inhibition prevents vascular leakage and lethality by blocking necroptotic signaling, preserving barrier function.^[50] FDA-approved inhibitors like phensuximide demonstrate robust protection in sepsis models by mitigating inflammation and bacterial load, with reduced serum cytokines such as CXCL1 in RIPK1-deficient contexts.^[52] These findings underscore RIPK1's amplification of JAK1-STAT3 pathways in lung injury during sepsis.^[62] Beyond specific diseases, RIPK1 regulates the NLRP3 inflammasome by integrating TNFR1 and TLR signaling to promote caspase-1 activation and IL-1β maturation, particularly through kinase-independent scaffolding that facilitates ASC oligomerization.^[63] In autoinflammatory contexts, RIPK1-RIPK3 complexes drive NLRP3-dependent pyroptosis and inflammation, as seen in response to microbial stimuli, while inhibitors disrupt this axis to curb excessive IL-1β.^[64] This regulatory role positions RIPK1 as a therapeutic target for NLRP3-hyperactive conditions like cryopyrin-associated periodic syndromes.^[65]

Oncological Implications

RIPK1 plays a dual role in cancer, acting as both a promoter of tumor progression through survival signaling and a potential target for inducing cell death in therapy-resistant malignancies. In its scaffold function, RIPK1 facilitates NF-κB activation downstream of TNF receptor signaling, thereby enhancing pro-survival pathways in tumor cells and contributing to oncogenesis.^[66] This mechanism supports tumor cell proliferation and metastasis, as observed in models where RIPK1 upregulation drives NF-κB-dependent expression of pro-angiogenic factors like VEGF-C.^[67] Additionally, RIPK1 inhibits necroptosis by phosphorylating RIPK3 or through caspase-8-mediated cleavage, which fosters chemotherapy resistance in cancers where apoptosis is evaded.^[68] For instance, in acute myeloid leukemia, suppression of spontaneous necroptosis via RIPK1 activity correlates with resistance to chemotherapeutic agents.^[69] Overexpression of RIPK1 has been documented in specific malignancies, notably colorectal and pancreatic cancers, where it exacerbates disease progression. In colorectal cancer, elevated RIPK1 levels promote mitochondrial calcium uptake via interaction with the mitochondrial calcium uniporter (MCU), boosting cellular respiration and tumor growth in patient-derived xenografts.^[70] Similarly, RIPK1 contributes to lymphatic metastasis in colorectal tumors by upregulating VEGF-C expression, with knockdown reducing migration and invasion in cell lines.^[71] In pancreatic cancer, RIPK1 kinase activity in the tumor microenvironment drives macrophage polarization toward an immunosuppressive phenotype, suppressing adaptive immune responses and enabling immune evasion.^[72] Beyond direct tumor effects, RIPK1 modulates inflammation in the tumor microenvironment by regulating cytokine production and immune cell recruitment, which can paradoxically support tumor progression through chronic inflammatory signaling.^[73] Conversely, targeting RIPK1 kinase activity holds anti-tumor promise by shifting signaling toward necroptosis, particularly in apoptosis-resistant cancers. Inhibition of RIPK1 with necrostatin-1 (Nec-1) or analogues blocks its pro-survival scaffold role, sensitizing caspase-8-deficient colorectal tumors to SMAC mimetic-induced necroptosis and leading to rapid tumor regression in mouse xenografts.^[74] This approach is effective in colon cancer models where RIPK3 is expressed, as RIPK1 inhibition allows RIPK3-MLKL complex formation to execute necroptotic cell death.^[75] Recent structure-activity relationship (SAR) studies in 2025 have optimized Nec-1 derivatives for enhanced potency in necroptosis induction, demonstrating selective killing of apoptosis-resistant colon carcinoma cells without affecting normal tissues.^[52] Therapeutic strategies exploiting RIPK1 inhibition are advancing, with small-molecule inhibitors showing preclinical efficacy against cancer and entering early clinical evaluation as of 2025. Compounds like phensuximide, an FDA-approved antiepileptic repurposed for RIPK1 targeting, inhibit kinase activity to promote necroptosis in tumor cells while sparing NF-κB-mediated survival in non-malignant contexts.^[52] PROTAC degraders specific to RIPK1 enhance immunogenic cell death and synergize with radiotherapy and immune checkpoint blockade in solid tumors, reducing tumor burden in mouse models.^[76] Pipeline agents such as Rigel's R552, following Phase I completion, are poised for Phase II trials, with potential applications in oncology through modulation of necroptosis and inflammation.^[77] In colorectal cancer, combining Met inhibitors like cabozantinib with SMAC mimetics stabilizes RIPK1 to enforce necroptosis, overcoming resistance in KRAS-mutant subtypes.^[78]

Protein Interactions

Key Binding Partners

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) engages key binding partners primarily through its death domain (DD) and receptor-interacting protein homotypic interaction motif (RHIM), facilitating recruitment into signaling complexes. The C-terminal DD of RIPK1 mediates homotypic interactions with other DD-containing proteins, enabling its association with tumor necrosis factor receptor 1 (TNFR1) and adaptor molecules such as TNFR1-associated DD protein (TRADD) and Fas-associated DD protein (FADD). Specifically, upon TNF stimulation, the intracellular DD of TNFR1 directly binds TRADD, which in turn recruits RIPK1 via DD-DD interactions to form complex I at the plasma membrane; this binding is essential for RIPK1 ubiquitination and scaffolding.^[19] In the absence of ubiquitination or under specific conditions, RIPK1 can also interact with FADD through DD-mediated dimerization, contributing to the assembly of complex II.^[12] The N-terminal RHIM of RIPK1 enables amyloid-like fibril formation and interactions with other RHIM-containing proteins, promoting oligomerization. RIPK1 binds receptor-interacting serine/threonine-protein kinase 3 (RIPK3) via RHIM-RHIM contacts, allowing trans-autophosphorylation and higher-order complex formation. Similarly, Z-DNA-binding protein 1 (ZBP1) interacts constitutively with RIPK1 through RHIM-RHIM interactions to facilitate delivery of RIPK1 to TRIF in Toll-like receptor (TLR) signaling; this complex promotes mitogen-activated protein kinase (MAPK)-mediated phosphorylation of RIPK1 at Ser321.^[79] TIR-domain-containing adapter-inducing interferon-β (TRIF) also engages RIPK1 via RHIM-mediated oligomerization, particularly in response to Toll-like receptor 3/4 activation, facilitating signal propagation.^[79] RIPK1 associates with kinase regulators that modulate its activity through phosphorylation, often via scaffold interactions. The IκB kinase (IKK) complex, including the regulatory subunit NF-κB essential modulator (NEMO), binds polyubiquitinated RIPK1, where NEMO recognizes K63-linked ubiquitin chains on RIPK1's intermediate domain to recruit IKKα/β for subsequent phosphorylation events.^[80] Transforming growth factor-β-activated kinase 1 (TAK1) interacts with RIPK1 indirectly through TAB2/3 adaptors that bind K63-ubiquitinated RIPK1, enabling TAK1 to phosphorylate RIPK1 at specific serine residues in its intermediate domain.^[81] Interactions with ubiquitin machinery components regulate RIPK1's ubiquitination status via attachment or removal of ubiquitin chains. The linear ubiquitin chain assembly complex (LUBAC), comprising heme-oxidized IRP2 ubiquitin ligase-1 (HOIL-1) and HOIP (RNF31), binds RIPK1 through HOIP's recognition of ubiquitinated RIPK1 or TNFR1 complex components, catalyzing M1-linked linear ubiquitination on RIPK1's lysine residues to stabilize signaling platforms. Deubiquitinases such as cylindromatosis (CYLD) and A20 (TNFAIP3) counteract this by binding RIPK1; CYLD specifically removes M1-linked chains from RIPK1 via its catalytic domain, recruited through interactions with linear ubiquitin structures, while A20 acts as an OTU deubiquitinase targeting K63 chains on RIPK1, often in concert with its zinc finger domains for substrate specificity.^[82]

Regulatory Complexes

RIPK1 plays a central role in assembling dynamic multi-protein complexes that dictate cellular outcomes in response to TNF receptor 1 (TNFR1) signaling, transitioning from pro-survival to pro-death configurations based on post-translational modifications and environmental cues.^[83] Complex I, also known as the TNF receptor signaling complex (TNF-RSC), forms at the plasma membrane upon TNF binding to TNFR1 and promotes NF-κB-mediated survival signaling. This complex includes RIPK1, TRADD, TRAF2, cellular inhibitors of apoptosis proteins (cIAPs), the linear ubiquitin chain assembly complex (LUBAC), and NEMO, where RIPK1 serves as a scaffold ubiquitinated by cIAPs and LUBAC to recruit downstream kinases like TAK1 and IKK for transcriptional activation.^[83] The stability of Complex I prevents RIPK1's release and maintains cell viability under homeostatic conditions. Upon deubiquitination of RIPK1 by CYLD or in the presence of caspase inhibitors, Complex I dissociates, allowing RIPK1 to translocate to the cytosol and form Complex IIa, a caspase-8-activating apoptosome that drives extrinsic apoptosis. Complex IIa comprises RIPK1, FADD, and caspase-8, where FADD bridges RIPK1's death domain to caspase-8's death effector domain, enabling caspase-8 dimerization and auto-activation to initiate the caspase cascade.^[7] This complex operates independently of RIPK1 kinase activity, emphasizing RIPK1's scaffolding function in apoptosis induction when survival signals are insufficient.^[7] In scenarios where caspase-8 activity is blocked, such as by viral inhibitors or genetic ablation, RIPK1 instead assembles the necrosome, or Complex IIb, to execute necroptosis, a lytic form of programmed cell death. The necrosome core consists of RIPK1 and RIPK3, which oligomerize via their RIP homotypic interaction motifs (RHIMs) into a hetero-amyloid structure, with RIPK3 autophosphorylation recruiting and activating MLKL to permeabilize the plasma membrane. Structural studies reveal this core as a serpentine β-sheet fold stabilized by a Cys-Ser ladder, highlighting its amyloid-like signaling properties essential for necroptotic execution.^[84] Beyond binary death outcomes, RIPK1 participates in the PANoptosome, an integrated platform that coordinates PANoptosis—a unified inflammatory cell death pathway merging pyroptosis, apoptosis, and necroptosis features—triggered by innate immune sensors like ZBP1 during viral infections or sterile inflammation. The PANoptosome incorporates RIPK1 with ZBP1, ASC, and multiple caspases (including caspase-1, -6, and -8), where ZBP1 acts as a scaffold to recruit RIPK3 and NLRP3 inflammasome components via RHIM and CARD interactions, amplifying cytokine release and lytic death.^[85] Recent structural analyses using expansion microscopy and co-immunoprecipitation have elucidated its modular assembly, revealing RIPK1's role in bridging necroptotic and pyroptotic effectors within a single megacomplex, distinct from isolated pathway complexes. This integration allows context-dependent cell death, enhancing immune responses but contributing to pathology when dysregulated.

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[13]
Autophosphorylation at serine 166 regulates RIP kinase 1-mediated ...
Apr 8, 2020 · Here we show that RIPK1 autophosphorylation at serine 166 plays a critical role for the activation of RIPK1 kinase-dependent apoptosis and necroptosis.Missing: Thr189 IKKβ
[14]
The latest information on the RIPK1 post-translational modifications ...
RIPK1 is a protein kinase that simultaneously regulates inflammation, apoptosis, and necroptosis. It is thought that RIPK1 has separate functions through ...
[15]
Regulation of RIPK1 Phosphorylation: Implications for Inflammation ...
RIPK1 controls inflammation and cell death. Phosphorylation regulates its activity, switching between cell survival and death. Perturbations in phosphorylation ...
[16]
https://www.sciencedirect.com/science/article/pii/S0753332221008659
[17]
Ubiquitination of RIPK1 regulates its activation mediated by TNFR1 ...
Dec 11, 2020 · RIPK1 is a death-domain (DD) containing kinase involved in regulating apoptosis, necroptosis and inflammation. RIPK1 activation is known to ...Missing: boundaries | Show results with:boundaries
[18]
RIP1 post-translational modifications | Biochemical Journal
While RIP1 scaffold controls of MAPK and NF-κB signaling pathways at TNFR1 complex I, the formation and function of pro-death complex II is regulated by RIP1 ...
[19]
Characterization of Novel Pathogenic Variants Leading to Caspase ...
The caspase-8 binding and cleavage site occurs at the 321LQLD324 sequence of RIPK1, and the cleavage process separates the kinase domain from the intermediate ...
[20]
https://portlandpress.com/biochemj/article/479/9/929/231273/RIP1-post-translational-modifications
[21]
https://pmc.ncbi.nlm.nih.gov/articles/PMC9674708/
[22]
https://doi.org/10.1007/s10875-022-01298-2
[23]
In TNF-stimulated Cells, RIPK1 Promotes Cell Survival by Stabilizing ...
In this way, RIPK1 was proposed to promote cell survival by allowing activation of the canonical NF-κB. ... TNF induces non-canonical NF-κB in RIPK1−/− MEFs.
[24]
The resurrection of RIP kinase 1 as an early cell death checkpoint ...
Sep 28, 2022 · The pro-survival role of RIPK1 in maintaining cell survival is achieved via its ability to induce NF-κB-dependent expression of anti-apoptotic ...
[25]
NFκB and ubiquitination: partners in disarming RIPK1-mediated cell ...
Apr 5, 2012 · In this review, we will discuss how NFκB and ubiquitination operate as two major pro-survival signaling mechanisms that control cell fate in the ...Nfκb-Independent... · Rip Kinases And Programmed... · Caspase 8 Removes Cyld...
[26]
Phosphorylation of cell cycle and apoptosis regulatory protein-1 by ...
May 1, 2024 · Genotoxic stress-induced ATM kinase activates the NF-κB pathway, which regulates genes involved in inhibition of apoptosis and promotion of cell ...
[27]
Kinase-independent functions of RIPK1 regulate hepatocyte survival ...
Jun 19, 2017 · RIPK1 was suggested to be important for NEMO-dependent activation of prosurvival NF-κB signaling in response to DNA damage (25). Moreover, ...
[28]
Primidone blocks RIPK1-driven cell death and inflammation - Nature
Dec 3, 2020 · The scaffolding function of the receptor-interacting serine/threonine protein kinase 1 (RIPK1) regulates pro-survival signaling and ...
[29]
RIPK3 signaling and its role in regulated cell death and diseases
Apr 29, 2024 · This review summarizes recent studies on the mechanisms of the RIPK3 signaling pathway, discusses the key role of RIPK3 in disease treatment and tumorigenesis,Role Of Ripk3 In Necroptosis · Ripk3 Induces Inflammasome... · Role Of Ripk3 In Cancer
[30]
Recent findings regarding novel necroptosis regulators - Nature
Jun 1, 2021 · When caspase-8 is inhibited, RIPK1 and RIPK3 form necrosome complexes through homotypic interactions with RHIM, resulting in the activation of ...Missing: paper | Show results with:paper
[31]
Caspases as master regulators of programmed cell death: apoptosis ...
Jun 24, 2025 · Post-translational modifications (PTMs) of caspases are essential for controlling their enzymatic activity, stability, subcellular localization ...
[32]
Intrinsic cleavage of receptor-interacting protein kinase-1 by ... - Nature
Aug 3, 2012 · We show that ubiquitously expressed caspase-6 has a supporting role in apoptosis by cleaving this kinase, thus preventing production of inflammatory cytokines.
[33]
Mitochondrial orchestration of PANoptosis: mechanisms, disease ...
Oct 21, 2025 · The kinase activity of RIPK1 is further enhanced through interaction with ZBP1, amplifying PANoptosome assembly [50, 52].Mitochondria And Apoptosis · Mitochondrial Dna Release... · Mitochondria In Mtor...
[34]
The impact of PANoptosis-related genes on immune profiles and ...
Oct 24, 2025 · Depending on the initial trigger, distinct PANoptosome complexes can form—such as the ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosomes—each ...
[35]
Molecular vulnerabilities for targeting inflammatory cell death in ...
Sep 13, 2025 · In this review, we present a novel, sensor-specific dissection of PANoptosome architecture, detailing how distinct innate immune sensors-ZBP1, ...
[36]
Z-DNA-binding protein 1 exacerbates myocardial ischemia ... - Nature
Oct 7, 2025 · Compared with treatment with conventional cell death inhibitors, cardiomyocyte-specific Zbp1 deficiency ameliorated I/R-induced PANoptosis, ...Zbp1 Deficiency Attenuates... · Zbp1 Induces Cardiomyocyte... · Msb Is A Novel Zbp1...
[37]
The double-edged functions of necroptosis | Cell Death & Disease
Feb 27, 2023 · Cylindromatosis (CYLD) and A20 are two crucial regulators of inflammatory signaling and cell death; both can remove the K63 polyubiquitin chain ...
[38]
CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell ...
Mar 31, 2017 · CYLD, A20 and OTULIN have been implicated as key DUBs in the negative regulation of NF-κB transcription factor-mediated gene expression.
[39]
RIPK1 mediates a disease-associated microglial response ... - PNAS
Sep 13, 2017 · This study demonstrates that RIPK1-dependent transcription promotes DAM and lysosomal defects to mediate the accumulation of amyloid plaques in AD.
[40]
Aβ oligomers trigger necroptosis-mediated neurodegeneration via ...
Mar 9, 2022 · These findings suggest that Aβo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration.
[41]
Safety, Pharmacokinetics and Target Engagement of a Novel Brain ...
Feb 17, 2025 · SIR9900 is a potent and selective novel small molecule RIPK1 inhibitor. This first-in-human, phase I, randomized, double-blind, placebo-controlled study
[42]
https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-022-01332-9
[43]
Yuan Lab discovers the role of RIPK1 in mediating axonal ...
Aug 15, 2016 · Furthermore, RIPK1/RIPK3-mediated axonal pathology was commonly observed in SOD1G93A transgenic mice and pathological samples from human ALS.<|separator|>
[44]
https://www.cell.com/neuron/fulltext/S0896-6273(14)00016-6
[45]
Targeting RIPK1 for the treatment of human diseases - PNAS
Importantly, the kinase activity of RIPK1 plays a central role in mediating multiple deleterious inflammatory cell death mechanisms upon the activation of TNFR1 ...Targeting Ripk1 For The... · Control Of Ripk1... · Developing Ripk1 Inhibitors...
[46]
RIPK1 in the inflammatory response and sepsis - PubMed Central
Apr 5, 2023 · Therefore, RIPK1 inhibition may be another means of alleviating the cytokine storm associated with sepsis. However, studies of RIPK1 in ...
[47]
RIPK1 mutations causing infantile-onset IBD with inflammatory and ...
We present the clinical features, genetic analysis and immune work-up of two patients with infantile-onset inflammatory bowel disease (IBD) resulting from RIPK ...
[48]
FDA-approved phensuximide inhibits RIPK1-dependent ... - Nature
Jun 2, 2025 · Notably, inhibition of the RIPK1 kinase has shown significant promise in providing robust and consistent protection against sepsis, mitigating ...
[49]
Very-early-onset Inflammatory Bowel Disease in an Infant with a ...
Apr 27, 2024 · Here, we discuss an infant with malnutrition, VEO-IBD, recurrent infections and polyathritis who has a homozygous partial deletion in RIPK1 gene.
[50]
Very Early Onset of Fistulizing Inflammatory Bowel Disease With ...
Mar 7, 2024 · Monogenic mutations have been linked to IBD. One of these mutations is RIPK1 mutation which should be suspected in patients with VEO-IBD ...
[51]
Neonatal onset inflammatory bowel disease and immunodeficiency ...
Apr 1, 2025 · We found that the disease onset time was extremely early in patients with biallelic RIPK1 variants. All patients developed symptoms within 9 ...
[52]
Identification the role of necroptosis in rheumatoid arthritis by ...
Jun 13, 2024 · This process mediated by RIPK1, RIPK3, and MLKL, can elicit significant inflammation and has emerged as a regulatory mechanism in various ...
[53]
KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1 ...
Mar 12, 2023 · This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options.Abstract · Introduction · Materials and methods · Results
[54]
KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1 ...
Mar 13, 2023 · Recent studies have shown that RIPK1-dependent necroptosis plays an important role in autoimmune diseases, including RA (4, 5). Clinical studies ...
[55]
Inhibition of receptor interacting protein kinase-1 (RIPK1 ... - PubMed
Jun 21, 2024 · RIPK1 inhibition has a protective effect in the mouse model of SLE and can potentially become a new therapeutic target for SLE in humans.
[56]
Receptor interacting protein kinase 1 activation and triggering ...
Here, we investigate the role of RIPK1 kinase activity in the pathogenesis of LN. Immunofluorescent colocalization of necroptosis with podocyte, endothelial ...
[57]
RIP kinase 1–dependent endothelial necroptosis underlies systemic ...
Apr 16, 2018 · Our results provide genetic evidence that RIPK1 kinase activity mediates endothelial cell necroptosis during TNF/zVAD-induced shock.
[58]
RIPK1 Drives JAK1‐STAT3 Signaling to Promote CXCL1‐Mediated ...
Sep 15, 2025 · This article examines the central role of RIPK1 in the pathogenesis of sepsis-induced lung injury. It elucidates how RIPK1 initiates an ...
[59]
RIPK1 and RIPK3 driven NLRP3 inflammasome activation and ...
RIPK1 and its kinase activity have long been understood to regulate inflammatory signalling, as well as both apoptotic and necroptotic cell death. However, ...
[60]
Multiple TLRs elicit alternative NLRP3 inflammasome activation in ...
Together these data suggest that the alternative pathway operates independently of RIPK1 kinase activity, downstream of diverse TLRs including TLR4 in primary ...
[61]
An update on the regulatory mechanisms of NLRP3 inflammasome ...
Apr 13, 2021 · NLRP3 inflammasome activation is regulated through a two-step process, with priming at the transcriptional and posttranslational levels (Signal 1) and assembly ...
[62]
RIPK1 Regulates Cancer Resistance to Immune Checkpoint Blockade
Cancer cell RIPK1 promotes TNF-mediated cell survival and NF-kB signaling rather than cell death ... In RIPK1 wildtype (WT) tumors, the NF-kB signaling kinase ...
[63]
https://www.sciencedirect.com/science/article/abs/pii/S1084952119302332
[64]
Bypassing drug resistance by triggering necroptosis
Dec 12, 2018 · Necroptosis is caspase-independent and controlled by RIPK1, RIPK3 and MLKL, which can be blocked by various specific small molecule inhibitors ( ...Main Text · Necroptosis And Inflammation... · Acute Myeloid Leukemia
[65]
Necroptosis in cancer: insight from epigenetic, post-transcriptional ...
Jul 30, 2025 · The kinase activity of RIPK1 induces caspase-8 dependent apoptosis and RIPK3/MLKL-dependent necroptosis, while the scaffolding function of RIPK1 ...<|control11|><|separator|>
[66]
RIPK1 Binds MCU to Mediate Induction of Mitochondrial Ca
Jun 1, 2018 · We report here that RIPK1 is upregulated in human colorectal cancer and promotes cell proliferation when overexpressed in a colon cancer cell ...
[67]
RIP1 Contributes to Colorectal Cancer Progression and Lymphatic ...
Sep 22, 2025 · RIP1 was found to be elevated in CRC tissues and positively associated with VEGF‐C expression. Knockdown of RIP1 reduced cell growth, migration, ...Missing: RIPK1 | Show results with:RIPK1
[68]
RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune ...
Oct 12, 2020 · RIP1 inhibition resulted in immunogenic macrophage differentiation in pancreatic cancer, leading to adaptive immune activation and tumor ...Missing: colorectal | Show results with:colorectal
[69]
Tumor Intrinsic & Immune Modulatory Roles of RIPKs
Apr 1, 2023 · Pro-survival function of RIPK1 in cancer. Although most studies indicate that RIPK1 exerts cytostatic effects on tumors, it can also promote ...
[70]
Regression of apoptosis-resistant colorectal tumors by induction of ...
May 5, 2017 · Recent studies have indicated that caspase-8 is frequently inactivated in human cancers via multiple mechanisms, including gene mutations, ...<|separator|>
[71]
Necroptosis in tumorigenesis, activation of anti-tumor immunity, and ...
Aug 30, 2016 · In the presence of cFLIPL, caspase-8 is unable to initiate apoptosis but can cleave RIPK1 and RIPK3 and thus inhibits necroptosis. Depletion of ...Necroptosis Backs Up Tumor... · Necroptosis In Cancer... · Necroptosis As A Cancer...
[72]
A RIPK1-specific PROTAC degrader achieves potent antitumor ...
May 23, 2024 · A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death.
[73]
RIPK1 Inhibitor Pipeline Outlook Report 2025: Key 10+ Companies ...
Aug 11, 2025 · Rigel's lead RIPK1 inhibitor, R552, has completed Phase I clinical trials and the planning to begin Phase II clinical trials is underway as part ...
[74]
Targeting the Met-RIPK1 signaling axis to enforce apoptosis and ...
Oct 20, 2025 · In addition, we show that it is feasible to modulate between apoptosis and necroptosis to overcome therapy resistance and foster anti-tumor ...
[75]
ZBP1 promotes inflammatory responses downstream of TLR3/TLR4 ...
Jun 6, 2022 · We previously reported that ZBP1 interacts with the TLR3/4 adaptor protein TRIF to promote RIPK1-mediated cell death (10). Since RIPK1 also ...
[76]
Regulation of RIPK1 activation by TAK1-mediated phosphorylation ...
Aug 25, 2017 · Here, we report that TNFα-induced phosphorylation of RIPK1 in the intermediate domain by TAK1 plays a key role in regulating this critical decision.
[77]
https://www.theglobeandmail.com/investing/markets/markets-news/GetNews/34058091/ripk1-inhibitor-pipeline-outlook-report-2025-key-10-companies-and-breakthrough-therapies-shaping-the-future-landscape/