Cell Death & Differentiation

Ferroptosis, an intracellular iron-catalyzed form of programmed cell death (PCD) driven by lipid reactive oxygen species induced membrane damage, is mechanistically uncharacterized in its execution process. Here, we investigated ferroptosis execution in mesenchymal-like ovarian cancer cells treated with ferroptosis inducers ML162 and erastin. We showed that YVAD (a pyroptosis-associated inflammatory caspase inhibitor) and disulfiram (preventing gasdermin pore formation on plasma membrane) deterred ferroptotic cell death. Moreover, we also observed LDH release and IL-1{beta} secretion from ferroptotic cells, suggesting that ferroptosis involves a pore-forming process. Intriguingly, ferroptosis is independent of the canonical inflammasome pathway because caspase-1 is dispensable and not activated upon ferroptosis induction. In contrast, we found that caspase-5 was activated while caspase-4 was not during ferroptosis. In addition, depletion of caspase-5 rendered cells not responding to ferroptosis inducers. Also intriguingly, GSDMD, the well-established caspase-5 substrate, was not involved in ferroptosis. We instead detected GSDME cleavage upon ferroptosis induction and knockdown of GSDME reduced cell death induced by ferroptosis inducers. As caspase-5 activity was necessary for ferroptosis and caspase-5 directly cleaved GSDME, we conclude that the axis of caspase-5/GSDME executes ferroptosis in ovarian cancer cells.

Mouse models have historically been central to studies of TNF-induced cell death and guided pharmaceutical translation into clinic, based on the assumption that TNF signaling is conserved between human and mouse. Here, our work uncovers critical species-specific differences between the two. By systematically dissecting the roles of RIPK1, TRADD, and sensitivity to RIPK1 inhibitors in TNF signaling--including RIPK1 kinase-dependent and-independent apoptosis--we found that both apoptosis modalities diverge between human and mouse cells. In mouse cells, RIPK1 suppresses TRADD-mediated kinase-independent apoptosis, whereas in human cells, RIPK1 and TRADD act redundantly. Moreover, RIPK1 inhibitors block kinase-dependent apoptosis in mouse but not human cells, despite effectively inhibiting RIPK1 S166 phosphorylation. Cross-species complementation revealed that these discrepancies stem not from RIPK1 itself but from cell-context differences. These findings echo the clinical failures of RIPK1 inhibitors despite efficacy in mouse models and underscore the need for humanized models and therapeutics that more faithfully predict clinical outcomes.

TP53 (also called TRP53 or p53) is a critical tumour suppressor that prevents cancer development by inducing a transcriptional program which can lead to diverse cellular responses, most prominently, cell proliferation arrest/senescence with survival of cells or cell death by apoptosis. Why distinct cell types undergo different outcomes after p53 activation remains unclear. Using integrated RNA-sequencing, proteomic and functional analyses across a diverse range of murine primary cell types, we demonstrate that cell fate is governed by the balance between pro-survival BCL-2 and pro-apoptotic BH3-only proteins. Cells resistant to apoptosis displays a higher starting ratio of pro-survival BCL-2 to pro-apoptotic BH3-only proteins, along with transcriptional upregulation of the pro-survival gene Bcl2l1, encoding BCL-XL. This control of cell fate is also seen in human wild-type p53 cancer cell lines. These findings reveal the mechanism for understanding p53-driven cell fate decisions, suggest therapeutic strategies to shift p53-induced cell proliferation arrest/senescence toward apoptotic cell death and allowed generation of an RNAseq data-based predictor of outcome for cancer cells after p53 activation.

Although KRAS G12C-specific inhibitors such as sotorasib have been approved by US FDA and currently used in clinic, treating non-G12C mutants and overcoming acquired resistance for these inhibitors remain critical challenges. Here, we introduce a reciprocal feedback blockade therapy combining the MEK inhibitor trametinib and the multi-tyrosine kinase inhibitor imatinib to overcome these limitations. Our study reveals their compensatory roles: trametinib suppresses MEK activity yet promotes tyrosine kinase signaling and angiogenesis, while imatinib, a pan-tyrosine kinase inhibitor unleashes the MEK/ERK pathway via phosphatase suppression. Combining these agents blocks the reciprocal survival signals, inducing robust cell death across diverse KRAS-mutant models. Mechanistically, this combination reprograms cellular metabolism, leading to autophagy-dependent lipid peroxidation accumulation and ferroptosis. This strategy was effective in sotorasib-resistant lung cancer cells and various mouse models, including pancreatic cancer patient-derived xenograft. Furthermore, a pilot clinical trial for KRAS-mutant pancreatic cancer yielded encouraging responses. Consequently, the trametinib-imatinib combination represents a promising, broad-spectrum therapeutic strategy to overcome the constraints of current KRAS-targeted therapies.

Cellular material in apoptotic cells must be efficiently cleared by phagocytes to maintain tissue homeostasis. Defects in this process can lead to the onset of secondary necrosis and the release of intracellular contents such as damage associated molecular patterns (DAMPs) and autoantigens that are often derived from the nucleus. Therefore, appropriate handling and clearance of apoptotic material is vital to prevent unwanted inflammatory response and the onset of autoimmune disorders. However, how nuclear material is packaged by apoptotic cells for effective clearance by phagocytes is not well understood. By utilising murine models of apoptosis, we observed that a distinct subset of large extracellular vesicles generated from apoptotic thymocytes, known as apoptotic bodies (ApoBDs), can harbour the majority of nuclear contents. Mechanistically, we discovered that apoptotic cells can asymmetrically partition the nucleus into a single large membrane bleb located at one side of the cell, with other cellular contents such as mitochondria and acid organelles distributed to the opposite side. Whilst this newly observed apoptotic morphology, coined as asymmetric cell death morphology (AsyCDM), is morphologically similar to the process of erythroblast enucleation, pharmacological compounds that could interfere with erythroblast enucleation did not block the establishment of AsyCDM during apoptosis. Notably, AsyCDM was reliant on the contractile forces generated by ROCK1-dependent plasma membrane blebbing. Taken together, this study suggests that intracellular contents are partitioned into different ApoBD subsets during apoptosis through a regulated process driven by ROCK1-dependent actomyosin contraction.

The transition from tumor necrosis factor (TNF)-induced plasma membrane-bound complex I to cytosolic death-inducing complex II switches cells from survival to death. However, the precise regulation of this fatal decision is incompletely understood. Here, we show that mTORC1 promotes this transition by destabilizing later-stage complex I without affecting its initial assembly. Inhibition of mTORC1 unleashes ATG9A and FIP200 activity, thereby promoting the accumulation of CHUK (IKK) in complex I. CHUK scaffolds the kinase-active IKK{beta} to stabilize complex I and prevent complex II formation. Activation of this ATG9A/FIP200-CHUK/IKK{beta} axis protects against TNF-induced fulminant hepatitis while compromises antibacterial defense against Staphylococcus aureus. This mTORC1-governed life-or-death transition provides therapeutic insight into TNF-related pathologies--including cancer, metabolic tissue injury, and microbial infections--where mTORC1 activity is frequently suppressed.

The liver is a metabolic hub with a high protein turnover that renders it uniquely susceptible to proteotoxic stress. Perturbation of proteostasis, either by proteasomal inhibitors or in chronic liver diseases, could adversely impact liver physiology. Here, we show that proteasomal inhibition unexpectedly suppresses basal type I interferon (IFN-I) signaling in the murine liver. Proteasomal inhibition by bortezomib selectively downregulates a subset of interferon-stimulated genes (ISGs), among which USP18 and ISG15 emerge as critical determinants of hepatocellular survival. We identify USP18 as a central cytoprotective factor that prevents proteotoxic apoptosis independently of its deubiquitinase activity, but strictly requires its scaffolding function mediated by isoleucine-60 and interaction with STAT2. Mechanistically, proteotoxic stress disrupts IRF9 nuclear translocation, attenuating USP18 transcription, and drives USP18 and other ISGs into insoluble aggregates with kinetics distinct from canonical IFN-I-induced insolubility. Strikingly, IFN-I priming preserves ISG solubility, restores USP18 abundance, and confers resistance to proteotoxic cell death. Together, these findings uncover an unanticipated link between proteostasis and innate immune signaling, and establish the USP18-STAT2 axis to enhance hepatic resilience under proteotoxic stress.

Nicotine accumulates in the gut and drives non-alcoholic steatohepatitis (NASH) via the gut-liver axis, yet no effective clinical intervention is currently available. To address this challenge, the probiotic Escherichia coli Nissle 1917 (EcN) was engineered for in situ nicotine clearance in the gut. Mutational screening of nicotine oxidoreductase 2 (PpNicA2) identified a highly active variant, PpNicA2A107R. Its incorporation into EcN together with an electron transfer protein (CycN) and a newly identified transporter (T3/T7) yielded 80% nicotine-degrading activity. Chromosomal integration of this module generated a stable strain, EcN-N12, which in NASH mouse models depleted intestinal nicotine, rescued hepatic lipid metabolism, alleviated tissue damage, and intercepted the nicotine-mediated gut-liver axis pathological progression. This work thus offers an effective and clinically translatable approach for nicotine-associated diseases.

Gasdermins are pore-forming effectors that mediate pyroptosis, an inflammatory form of programmed cell death characterized by membrane permeabilization and the release of intracellular contents. Phylogenetically, gasdermin members can be broadly divided into two major branches, the GSDME/PJVK branch and the GSDMA/B/C/D branch. Whereas the GSDME mediated pyroptosis was traced back to metazoans, the functional origins of GSDMA/B/C/D branch remain poorly understood. As a basal representative of the GSDMA-D lineage in cartilaginous fish, Callorhinchus milii GSDMA/B (CmiGSDMA/B) provides essential information for the ancestral state of this branch. Here, we functionally characterized CmiGSDMA/B and identified CmiCASP1 as its upstream protease. Mechanistically, Lipopolysaccharide (LPS) activates CmiCASP1 via its CARD domain, leading to cleavage of CmiGSDMA/B into two functionally distinct products, N241 and N288. N241 binds cell membrane to drive pyroptosis, whereas N288 suppresses N241-triggered cell death. Interestingly, N241 exhibits bactericidal activity against Gram-negative bacteria in vitro, suggesting that antimicrobial activity may have been an early feature of the GSDMA-D lineage. Collectively, these findings provide insight into a non-canonical, LPS-responsive, caspase-driven pyroptosis pathway in cartilaginous fish and reveal the dual-fragment antagonistic regulation within this branch.

A-type lamins are critical for nuclear integrity and mechanotransduction in cardiomyocytes, and their disruption is a major cause of inherited cardiomyopathy. To compare the consequences of lamin A/C loss versus defective lamin A maturation, we generated CRISPR/Cas9-edited hiPSC lines lacking LMNA or ZMPSTE24 and differentiated them into iPSC-derived cardiomyocytes. LMNA knockout caused progressive nuclear deformation, loss of culture stability, and contractile vulnerability in iCM. ZMPSTE24 knockout led to subtler nuclear abnormalities and reduced calcium transient activity, temporally correlating with prelamin A accrual. Transcriptomics profiling revealed aberrant mechanical responses in both LMNA and ZMPSTE24 bi-allelic knockouts as well as unique perturbations in inflammatory signaling and epigenetic pathways. Interestingly, both knockout models shared a marked defect in proteostasis, as confirmed by reduced proteasome activity. Together, these results show that loss of lamin A/C and accumulation of prelamin A trigger both converging and distinct cardiomyocyte stress responses. In addition, the newly generated models offer an attractive platform to study lamin-associated cardiomyopathy and its therapeutic targeting.

Objectives; The role of nuclear receptor subfamily 4, group A, member 3 (NR4A3) in hepatic steatosis, inflammation, and insulin resistance (IR) within the context of metabolic dysfunction-associated steatotic liver disease (MASLD) remains largely underexplored. Consequently, this study aimed to examine NR4A3's impact on MASLD and the potential underlying mechanisms. Methods; We aimed to elucidate the functional role of NR4A3 in MASLD through its knockdown in cell culture and animal models. To establish the cell culture model of MASLD, LO2 cells were treated with free fatty acids (FFAs), while male C57BL/6 mice were fed a high-fat diet (HFD) to create the animal model. NR4A3 knockdown was achieved using specific short hairpin RNA (NR4A3-shRNA) in the mice model and three small interfering RNAs (NR4A3-siRNAs) in the cell culture model. The lipids content, fatty acid synthesis, inflammatory factors, and IR were then assessed with and without NR4A3 knockdown. Furthermore, the underlying mechanism through which NR4A3 exerts its influence was explored by analyzing the interaction between NR4A3 and activating transcription factor 3 (ATF3). Results: In the cell culture experiments, the knockdown of NR4A3 significantly decreased the lipids content, fatty acid synthesis, and inflammatory factors in the LO2 cells treated with FFAs in the NR4A3-shRNA group compared with those in the NC-shRNA control group. In the animal model experiments, NR4A3 knockdown in the HFD male C57BL/6 mice significantly ameliorated HFD-induced hepatic steatosis, inflammation, and IR. Mechanistically, the knockdown of NR4A3 downregulated the expression and transcriptional activity of ATF3, resulting in an impaired ATF3 function. ATF3 overexpression significantly reversed lipid accumulation decline and reduced inflammation after NR4A3 knockdown. Conclusion: The downregulation of NR4A3 alleviates MASLD by modulating ATF3, suggesting this may be a promising therapeutic target.

Necroptosis is best known as a lytic, proinflammatory cell-death pathway mediated by RIPK3 and MLKL. Effective wound repair requires the rapid resolution of inflammation, and ongoing necroptotic activity would only exacerbate tissue damage, delaying healing. However, damaged skin presents a trigger-rich environment for necroptotic signalling, an apparent paradox that remains unresolved. Using genetic ablation and pharmacological inhibition across multiple wound models, we show that inhibiting necroptosis accelerates wound closure, revealing that necroptotic signalling normally restrains repair. Surprisingly, we found that MLKL activation in wild-type keratinocytes induces differentiation and membrane repair rather than cell lysis. This adaptive, non-lethal mode of necroptotic signalling preserves barrier integrity but slows re-epithelialisation. Our findings redefine epidermal necroptotic signalling as a stress-responsive program that modulates keratinocyte fate in a trigger-rich environment. Temporarily dampening this pathway may enhance regeneration after barrier loss without compromising immune defence, revealing necroptosis as a tunable mechanism balancing tissue repair and inflammation.

Background: Pediatric chronic pancreatitis (CP) carries an elevated lifetime risk of pancreatic ductal adenocarcinoma (PDAC), yet the cellular and molecular mechanisms driving disease progression and early neoplastic transformation remain undefined. Methods: We performed single-nucleus RNA sequencing (snRNA-seq) on pancreatic tissue from 15 pediatric CP individuals and 6 healthy controls (HC). Findings were integrated with peripheral blood flow cytometry immunophenotyping of 8 CP and 7 HC individuals and validated by histopathological assessment. Findings: We identified 15 distinct cell populations and profound cellular remodeling in CP, including a 46% reduction in acinar cells and emergence of inflammatory fibroblasts as the dominant stromal population. Acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) populations bearing early PDAC-associated transcriptional signatures were detected in most CP samples. Cell-cell interaction analysis revealed that 68% of CP-specific ligand-receptor interactions converged on ADM and PanIN populations via ECM-integrin and inflammatory pathways. Peripheral blood flow cytometry demonstrated concordant systemic immune activation, including elevated monocyte CCR2 and CD80, increased CD69 on T cells, and upregulated ROR{gamma}t in regulatory T cells. Interpretation: This atlas defines the cellular landscape and intercellular signaling networks underlying pediatric CP, identifying inflammatory fibroblasts and early neoplastic cell states as central features. These findings provide a molecular foundation for understanding cancer risk in pediatric CP and provide a resource to prioritize studies into potential therapeutic targets and biomarkers. Funding: This work was supported by the Network for Pancreatic Organ donors with Diabetes (nPOD) and The Leona M. & Harry B. Helmsley Charitable Trust.

Genetic uniqueness of the tumor microenvironment significantly influences cancer growth, survival, and response to therapy, independent of the cancer cells intrinsic properties or the adaptive immune system. Using genetically distinct Rag1-/- mouse models, this study shows that different strains exhibit varied tumor growth kinetics and survival outcomes when xenografted with identical leukemic and solid tumor cell lines. This study further highlights the critical role of the myeloid immune compartment and shows that disrupting both lymphoid and myeloid systems alters cancer progression. These results also reveal that the tumor microenvironment can permanently alter cancer cell phenotypes and significantly affect chemotherapy efficacy, as seen with Cisplatins varying effects across strains. These findings underscore the importance of considering genetic background in preclinical cancer models, suggesting that reliance upon a single mouse strain may lead to incomplete conclusions about cancer biology and treatment efficacy. SUMMARY STATEMENTPre-clinical xenograft mammalian models are used to study human diseases. Here we report that the genetic uniqueness of the tumor microenvironment, independent of the immune system, can determine the fate of cancer progression, survival, and therapy response.

Gastric insulin-secreting organoids (GINS) represent a promising source of {beta}-like cells for type 1 diabetes (T1D) therapy. In same-donor comparisons with induced pluripotent stem cell-derived islets (iPSC-islets), GINS displayed robust glucose responsiveness and reduced expression of key T1D autoantigens. Importantly, GINS exhibited decreased susceptibility to cytotoxicity mediated by engineered HLA-matched preproinsulin-specific effector T cells (Avatar Teffs) and a distinct transcriptional profile enriched for immune-modulatory and stress-adaptive gene programs. To enhance immune evasion, we engineered gastric stem cells to overexpress Programmed Death Ligand 1 (PD-L1) in an inducible manner. PD-L1+ GINS maintained normal functionality, while exhibiting improved survival under allogeneic Avatar Teff challenge in a MHC class I-independent fashion. We evaluated PD-L1-mediated protection against autologous Avatar Teff attack using an endothelialized microfluidic platform recapitulating physiologic immune interactions. T cells show reduced infiltration into PD-L1 GINS, resulting in significantly higher organoid viability compared to control GINS. Together, these findings identify GINS as a functional and engineerable {beta}-like cell platform with intrinsic hypoimmunogenic features, and support PD-L1 engineering as a strategy to enhance immune protection for both allogeneic and autologous transplantation in T1D.

Type 1 diabetes (T1D) involves immune-mediated destruction of pancreatic {beta}-cells, yet current disease-modifying therapies mainly target immunity without enhancing {beta}-cell resilience. We show selective neuropeptide Y4 receptor (Y4R) agonism protects {beta}-cells while reshaping islet immunity across T1D models. Multi-modal localisation using cell sorting, qPCR, RNAscope and fluorescent ligand competition demonstrated predominant Y4R expression and functional accessibility on mouse and human {beta}-cells. Selective Y4R agonism was non-toxic and did not impair islet network integrity, Ca{superscript 2} dynamics, glucose-stimulated insulin secretion or systemic glucose tolerance. Y4R activation conferred cytoprotection against inflammatory cytokines, streptozotocin, lipotoxicity and ER stress, reducing caspase-3/7 activation and {beta}-cell loss whilst sustaining insulin release and promoting proliferation in both mouse and human islets. Bulk RNA-seq revealed a coordinated {beta}-cell resilience programme characterised by reinforced identity and insulin processing, KEAP1-NFE2L2-driven antioxidative and proteostatic activation, and suppression of EIF2 signalling and associated biosynthetic and ER stress pathways. Concurrently, Y4R agonism dampened pathogenic chemokine and cytokine networks, including CXCL10, CCL3/4/7 and IL-6, while preserving IL-2 and Foxp3 signals, thereby limiting CD8 T cell, CD4 T cell and macrophage chemotaxis toward cytokine-stressed islets. Reduced immune-cell recruitment was conserved in a fully human immune-islet system, where Y4R activation significantly attenuated IL-2-activated human PBMC migration and invasion toward cytokine-stressed human islets. In a stringent NY8.3 CD8 T cell adoptive-transfer model, systemic Y4R agonism significantly delayed diabetes onset. These data position Y4R as a {beta}-cell-centric therapeutic target coupling intrinsic resilience with local immune modulation, offering a complementary approach for {beta}-cell preservation in T1D and islet replacement therapies. Graphical abstractThe selective Y4 receptor agonist K22 binds {beta}-cell-enriched NPY4R in mouse and human islets, activates a {beta}-cell resilience programme that preserves insulin secretion under inflammatory and metabolic stress, and simultaneously dampens islet chemokine output, thereby limiting innate and adaptive immune-cell recruitment and delaying autoimmune diabetes onset. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/736290v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@11af8d3org.highwire.dtl.DTLVardef@1c60d37org.highwire.dtl.DTLVardef@18dd142org.highwire.dtl.DTLVardef@1a56cdb_HPS_FORMAT_FIGEXP M_FIG C_FIG

Hepatocellular carcinomas (HCC) are genetically heterogeneous cancers frequently characterized by MYC gene amplification or hyperactivating {beta}-catenin (CTNNB1) mutations. Analysis of TCGA transcriptomics revealed that MYC-driven HCC tumors have decreased expression of mtDNA-encoded genes, but increased expression of nuclear-encoded mitochondrial genes. To investigate this apparent discrepancy, we generated MYC- and CTNNB1-driven murine HCCs, all of which displayed aberrant mitochondrial metabolism. Notably, MYC-driven tumors exhibited significant reductions in OXPHOS and TCA cycle activity that correlated with increased ROS levels, as well as elevated mitochondrial turnover through mitochondrial fission and mitophagy. MYC induces the expression of nuclear respiratory factor 1 (NRF1), which regulates DRP1 and other genes to promote receptor-mediated mitophagy. Knocking out DRP1 reduced mitophagy and ROS levels and promoted survival of HCC-bearing mice. These results identify elevated mitochondrial turnover as a potential therapeutic target in MYC-driven HCC. SignificanceHepatocellular carcinoma can arise from multiple oncogenes, making targeted therapy more difficult. Here we show that tumors with MYC amplification lose mitochondrial function via fission and mitophagy upregulation. Targeting mitochondrial quality control results in increased survival suggesting a therapeutic window in MYC-driven HCC.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of cancer worldwide. While most cSCCs are not life-threatening, 2-5% of patients develop metastases. To better understand what causes some cSCCs to progress to metastatic disease, we assembled a nationwide cohort of 19,120 patients with clinico-pathologically annotated tumors linked to metastatic outcome. RNA-sequencing was performed on 378 tumors, and whole-exome sequencing on 147, with balanced numbers of tumors that progressed to metastatic disease (cases) and did not (controls). UV radiation was the dominant mutational signature with additional contributions from aging, APOBEC activity, and, in immunosuppressed patients, azathioprine exposure. We identified 38 genes under selection across a core set of signaling pathways. Gene expression clusters were primarily associated with the differentiation state of tumor cells and secondarily with the composition of the tumor microenvironment. Several mutational and transcriptional programs were associated with metastasis, including a dedifferentiated gene expression signature, activating mutations in the RAS signaling pathway, loss-of-function alterations in the SWI/SNF chromatin remodeling complex, and specific arm-level copy number alterations. A 23-gene expression signature was built to predict metastasis from primary cSCC tissue. The signature was validated in two independent cohorts (N=102 and 52), where it predicted metastasis independently of staging systems. Together, these findings provide the most detailed molecular portrait of cSCC to date and establish an assay for risk stratification suitable for clinical implementation.

Ferroptosis is driven by lipid peroxidation, yet the mechanisms by which cells rapidly adjust their sensitivity to ferroptosis in response to extracellular cues remain elusive. We identify a direct phosphorylation switch controlling the activity of glutathione peroxidase 4 (GPX4), the core ferroptosis regulator. The receptor tyrosine kinase FGFR1 directly binds and phosphorylates GPX4 at Tyr180/Tyr196 in a kinase-dependent manner, requiring its Tyr730 as a docking site. This phosphorylation enhances GPX4s catalytic activity and suppresses ferroptosis. In cardiac ischemia/reperfusion injury, the FGFR1-GPX4 axis is suppressed, and a selective FGFR1 agonist (FGF-1{Delta}NT) reactivates it to protect against ferroptosis-mediated damage. Critically, a phosphorylation-deficient GPX4 knock-in mouse exhibits hypersensitivity to injury and non-responsive to this agonist, proving that GPX4 phosphorylation is essential. Our findings reveal a rapid mechanism for regulating ferroptosis via GPX4 tyrosine phosphorylation, directly linking receptor tyrosine kinase signaling to ferroptosis, and offering new strategies for treating ischemic-and other ferroptosis-associated diseases.

Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.