bims-cediti 2025-09-07 papers

bims-cediti

Biomed News

on Cell death in innate immunity, inflammation, and tissue repair

Issue of 2025–09–07
thirteen papers selected by
Kateryna Shkarina, Universität Bonn

NINJ1 oligomerises on large apoptotic cell-derived extracellular vesicles to regulate vesicle stability and cellular content release.
Caspase cleavage of Kaposi sarcoma-associated herpesvirus proteins: a role for K5 in preventing caspase-mediated cell death during lytic replication.
Type A cholesterol-dependent cytolysins translocate to the trans-Golgi network for NLRP3 inflammasome activation.
Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease.
Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action.
Nigericin-Triggered Phosphodynamics in Inflammasome Formation and Pyroptosis.
Regulated cell death in fungi from a comparative immunology perspective.
HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation.
Differential cell survival outcomes in response to diverse amino acid stress.
Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling.
STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells.
5' cap sequestration is required for sensing of unspliced HIV-1 RNA by MDA5.
Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis.

Front Immunol. 2025 ;16 1599809

NINJ1 oligomerises on large apoptotic cell-derived extracellular vesicles to regulate vesicle stability and cellular content release.

Bo Shi, Caolingzhi Tang, Stephanie F Rutter, Omar Audi, Dilara C Ozkocak, Alice M Trenerry, Daniel S Simpson, Scott A Williams, Quan T Le, Gemma F Ryan, Ponsuge T M Cooray, James E Vince, Jason M Mackenzie, Mark D Hulett, Thanh Kha Phan, Ivan K H Poon.

  Billions of cells undergo apoptosis, a non-inflammatory form of programmed cell death, daily as part of normal development and homeostasis. Apoptotic cells undergo apoptotic cell disassembly to release large extracellular vesicles (EVs) called apoptotic bodies (ApoBDs) to promote dead cell clearance, or otherwise proceed to an inflammatory, lytic outcome (i.e., secondary necrosis). The latter event is regulated by ninjurin-1 (NINJ1), a key executioner of plasma membrane rupture (PMR) through its oligomerisation. However, the precise role of NINJ1 at the intersection of apoptotic cell disassembly and secondary necrosis remain elusive. Here, we show that NINJ1 increasingly oligomerises upon the completion of apoptotic cell disassembly process and that higher-order NINJ1 oligomerisation occurs on ApoBDs. We also demonstrate that NINJ1 regulates PMR of ApoBDs and the release of inflammatory signals and, in part, norovirus particles. Together, our findings provide new insights into NINJ1-mediated PMR and content release-associated functions of ApoBDs.

Keywords:  NINJ1; apoptosis; apoptotic bodies; extracellular vesicles (EVs); inflammation; norovirus; plasma membrane rupture

DOI:  https://doi.org/10.3389/fimmu.2025.1599809
J Virol. 2025 Aug 29. e0062225

Caspase cleavage of Kaposi sarcoma-associated herpesvirus proteins: a role for K5 in preventing caspase-mediated cell death during lytic replication.

David A Davis, Yana Astter, Emma N Treco, Prabha Shrestha, Alexandra Stream, Muzammel Haque, Naomi Mulugeta, Robert Yarchoan.

  Viral infections lead to caspase activation as a cellular defense response. Some viruses overcome this response by encoding viral proteins that undergo caspase cleavage and, by various mechanisms, aid in cell survival. Kaposi sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen acts as a pseudo-substrate for caspases-1 and -3, thereby interfering with the inflammatory and apoptotic response. Here, we screened the KSHV proteome for additional caspase cleavage sites. Using SitePrediction, many KSHV proteins with potential caspase cleavage sites were identified. Among the highest-scoring proteins was the early lytic protein, K5. Treatment of BJAB-K5-FLAG-expressing cells with ⍺Fas led to caspase processing of K5-FLAG. Using mass spectrometry, we determined that caspase cleavage of K5 occurs at D222. K5 was also cleaved by caspases when KSHV was induced to lytic replication. Interestingly, the expression of K5-FLAG significantly inhibited ⍺Fas-induced caspase-mediated cell death. To determine if K5 plays a protective role in KSHV-infected cells, iSLK cells infected with wild-type or K5-knockout BAC16 virus were induced to lytic replication. Although lytic induction showed no significant effect on the viability of wild-type-infected cells, the viability of K5-knockout cells decreased by 25%. Thus, K5 may protect KSHV-infected cells from caspase-mediated cell death during lytic replication. Interestingly, cleavage of K5 by caspases did not affect its previously reported ability to downregulate immune surface markers. These data suggest that K5 not only downregulates immune surface markers to help avoid immune recognition but plays an additional role in mitigating caspase-mediated cell death during lytic replication.IMPORTANCEKaposi sarcoma-associated herpesvirus (KSHV) is the etiological agent for Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and KSHV inflammatory cytokine syndrome. Understanding how KSHV thwarts host defense responses is necessary to help develop strategies to treat these rare, yet deadly, diseases. We profiled potential caspase cleavage sites in the viral proteome in silico and found many viral proteins with high-scoring caspase cleavage sites. We follow up on this by demonstrating that K5 is, in fact, a substrate for caspases in vitro and in cellulo and provide data to suggest that K5 plays a role in obviating caspase-mediated cell death during lytic replication. The work described here furthers our understanding of the roles that KSHV proteins, like K5, play to prevent or divert the host apoptotic defense responses that involve host caspase activation that normally would lead to cell death.

Keywords:  Kaposi sarcoma; MARCH-related protein; caspase; herpesvirus

DOI:  https://doi.org/10.1128/jvi.00622-25
Nat Immunol. 2025 Sep 05.

Type A cholesterol-dependent cytolysins translocate to the trans-Golgi network for NLRP3 inflammasome activation.

Nanyang Xiao, Airi Kogishi, Lisa Radochonski, Yuchong Lei, Jueqi Chen.

Cholesterol-dependent cytolysins (CDCs) constitute the largest group of pore-forming toxins and serve as critical virulence factors for diverse pathogenic bacteria. Several CDCs are known to activate the NLRP3 inflammasome, although the mechanisms are unclear. Here we discovered that multiple CDCs, which we referred to as type A CDCs, were internalized and translocated to the trans-Golgi network (TGN) to remodel it into a platform for NLRP3 activation through a unique peeling membrane mechanism. Potassium efflux was dispensable for CDC-mediated TGN remodeling and NLRP3 recruitment, but was required for the recruitment of the downstream adaptor ASC. In contrast, desulfolysin, which we referred to as type B CDC, was not internalized or translocated to the TGN due to its distinct C-terminal domain 4, despite potent pore formation on the plasma membrane, and hence could not activate NLRP3. Our discoveries uncovered the ability of CDCs to directly remodel an intracellular organelle for inflammatory response.

DOI: https://doi.org/10.1038/s41590-025-02277-6
Immunity. 2025 Aug 25. pii: S1074-7613(25)00333-4. [Epub ahead of print]

Innate immune sensing of Z-nucleic acids by ZBP1-RIPK1 axis drives neuroinflammation in Alzheimer's disease.

Ziwen Song, Xingxing Xie, Yulu Chen, Boxin Zhang, Xingyan Li, Yuanxin Yang, Wei Mo, Jian Zhang, Daichao Xu.

  Neuroinflammation drives Alzheimer's disease (AD) pathogenesis. Z-DNA, a non-canonical left-handed DNA structure, activates innate immune signaling through Z-DNA-binding protein 1 (ZBP1). However, the functional significance of ZBP1-mediated Z-DNA detection in AD remains undefined. Here, we found that ZBP1 is amplified in AD microglia, driving innate immune responses and neuroinflammation through sensing Z-form mitochondrial DNA (mtDNA). We show that oxidized mtDNA, generated by amyloid-β (Aβ)-induced oxidative stress, was fragmented and released into the cytoplasm, forming Z-DNA. Z-DNA-activated ZBP1 engaged receptor-interacting protein kinase 1 (RIPK1), promoting its kinase activation and inducing transcription of pro-inflammatory molecules and inflammatory signaling mediators. Genetic deletion of Zbp1 or inhibition of RIPK1 attenuated neuroinflammation, Aβ pathology, and behavioral deficits in an AD mouse model. Our findings reveal that oxidation induces the Z conformer in mtDNA and establish the ZBP1-RIPK1 axis as a key driver of AD neuroinflammation, providing insights into the immune mechanisms underlying AD pathogenesis and identifying a potential therapeutic target.

Keywords:  8-oxoguanine; Alzheimer's disease; DNA fragmentation; RIPK1; Z-DNA; ZBP1; amyloid-β; mitochondrial DNA; neuroinflammation; oxidative stress

DOI:  https://doi.org/10.1016/j.immuni.2025.07.024
J Exp Med. 2025 Nov 03. pii: e20242403. [Epub ahead of print]222(11):

Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action.

Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes, Maitriyee Mahanta, Matthew Banicki, Mary Cochran, Samantha Cowdin, Kristen Fortney, George Hartman, Robert E Hughes, Rusty Montgomery, Claudia P Portillo, Paul Rubin, Taiz Salazar, Yan Wang, Shijun Yan, Barry A Morgan, Assem Duisembekova, Romane Riou, Michael Marleaux, Inga V Hochheiser, Hannes Buthmann, Dominic Ferber, Jane Torp, Wei Wang, Melanie Cranston, Chloe M McKee, Thea J Mawhinney, Emma C McKay, Fehime K Eroglu, Jasmin Kümmerle-Deschner, Alexander N R Weber, Bénédicte F Py, Matthias Geyer, Rebecca C Coll.

The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.

DOI: https://doi.org/10.1084/jem.20242403
Proteomics. 2025 Sep 02. e70030

Nigericin-Triggered Phosphodynamics in Inflammasome Formation and Pyroptosis.

Vanya Bhushan, Clinton J Bradfield, Sandhini Saha, Sung Hwan Yoon, Iain D C Fraser, Aleksandra Nita-Lazar.

  Innate immune signaling relies heavily on phosphorylation cascades to mount effective immune responses. Although traditional innate immune signaling cascades following TLR4 stimulation have been investigated through a temporally quantitative phosphoproteomic lens, far fewer studies have applied these methods to distinct signaling following the inflammasome trigger leading to IL-1β release. Here, we conducted time-resolved phosphoproteomic profiling to investigate kinase signaling downstream of the inflammasome trigger nigericin. We found that nigericin induces rapid and potent alterations in the phosphorylation landscape where immune-related signaling, mitogen-activated protein kinases (MAPKs), and PKC signaling are prevalent. We also found significant evidence of phospho-modified metabolic cascades, suggesting that phosphosignaling plays a role in previously described immunometabolic regulation. These signaling events preceded robust phosphorylation of DNA damage and chromatin reorganization proteins before pyroptotic rupture. Lastly, by performing temporal clustering of phospho-dynamics, we revealed novel ontology-level shifts in phosphosignaling cascades following nigericin treatment that highlight abrupt changes in cellular behavior during early and late intracellular inflammatory events. SUMMARY: Protein phosphorylation is critical to convey innate immune signaling information to specific effector arms of the cellular immune response. This study focuses on characterizing phosphoproteomic alterations stemming from the inflammasome trigger nigericin. By gaining a deeper understanding of global kinase phosphodynamics in response to inflammasome activation, we aim to identify novel pharmacological targets to treat chronic inflammatory diseases driven by inflammasome-dependent IL-1β release.

Keywords:  MAPK; inflammasome; inflammation; phosphoproteomics; pyroptosis

DOI:  https://doi.org/10.1002/pmic.70030
Cell Death Differ. 2025 Sep 03.

Regulated cell death in fungi from a comparative immunology perspective.

Asen Daskalov.

The death of fungal cells has been studied in a variety of contexts including responses to antifungal drugs, during fungal developmental processes, in response to bacterial or mycoviral fungal pathogens, and during non-self-recognition between distinct strains of the same species (allorecognition). Some of the genetic determinants and molecular mechanisms of fungal cell death processes are now beginning to be understood in detail. Recent advances have uncovered fungal cell death machinery that shares ancestry with key actors of immune cell death in other eukaryotic and prokaryotic taxa. Transkingdom evolutionary links include fungal molecular sensors such as NOD-like receptors and signaling domains related to the TIR (Toll/interleukin-1 receptor) family, which are a staple of immunity throughout the tree of life. Moreover, cell death executioner proteins homologous to the pore-forming proteins that mediate mammalian necroptosis and pyroptosis are also abundant and widespread in fungi, particularly in Ascomycota. These findings prompt us to speculate on the possible origins of fungal cell death and to reconsider fungal innate immunity beyond allorecognition. This review discusses historical landmarks and major recent discoveries regarding the regulation of cell death processes in fungi through the lens of immunity.

DOI: https://doi.org/10.1038/s41418-025-01570-z
Cell Death Dis. 2025 Aug 28. 16(1): 656

HUMANIN produced by human efferocytic macrophages promotes the resolution of inflammation.

Mélissa Maraux, Mathieu Vetter, Ludivine Dal Zuffo, Francis Bonnefoy, Audrey Wetzel, Alexis Varin, Baptiste Lamarthée, Olivier Tassy, Didier Ducloux, Philippe Saas, Thomas Cherrier.

Elimination of apoptotic neutrophils by macrophages, a process called efferocytosis, is a critical step in the resolution of inflammation. Efferocytosis induces the reprogramming of macrophages towards a pro-resolving phenotype and triggers the secretion of pro-resolving factors. While mouse efferocytic macrophages are well-described, less is known about human efferocytic macrophages. Here, using RNA sequencing analysis of three different types of in vitro-derived human efferocytic macrophages, we observed a common modulation of mitochondrial metabolism-related genes in human M0, M1, and M2a-like macrophages, thus correlating with some previous results obtained in other non-human models. These results led us to identify for the first time some particular genes regulated in humans like PLIN5 and MTLN. We also shed light on a mitochondrial gene (MT-RNR2) coding a secreted factor called HUMANIN. Mainly known for its antioxidant and neuroprotective effects, we found that HUMANIN was also associated with pro-resolving properties in human and mouse models. Indeed, HUMANIN was produced early during the resolution of inflammation in an acute peritonitis mouse model. Preventive HUMANIN administration in this model reduced leukocyte infiltration and pro-inflammatory cytokine secretion. These anti-inflammatory properties were accompanied by the early acquisition of a CD11blow non-efferocytic phenotype by mouse macrophages and by an enhanced expression of pro-resolving genes including Alox15 and Retnla. The ability of HUMANIN to dampen pro-inflammatory cytokine secretion was also confirmed in primary human neutrophils. Finally, HUMANIN was also detected in gingival crevicular fluids of patients suffering from periodontitis after the onset of inflammation, suggesting a role of HUMANIN in the control of inflammation. Overall, our data shed light on new aspects of efferocytosis in humans and identify the pro-resolving potential of HUMANIN. This illustrates its prospective therapeutic interest in inflammatory disorders.

DOI: https://doi.org/10.1038/s41419-025-07909-1
Life Sci Alliance. 2025 Nov;pii: e202503324. [Epub ahead of print]8(11):

Differential cell survival outcomes in response to diverse amino acid stress.

Marion Russier, Alessandra Fiore, Ana Bici, Annette Groß, Maria Tanzer, Assa Yeroslaviz, Matthias Mann, Peter J Murray.

Amino acid (AA) detection is fundamental for cellular function, balancing translation demands, biochemical pathways, and signaling networks. Although the GCN2 and mTORC1 pathways are known to regulate AA sensing, the global cellular response to AA deprivation remains poorly understood, particularly in non-transformed cells, which may exhibit distinct adaptive strategies compared with cancer cells. Here, we employed murine pluripotent embryonic stem (ES) cells as a model system to dissect responses to AA stress. Using multi-omics analyses over an extended time course, we examined the effects of arginine (Arg) and leucine (Leu) deprivation. We uncovered a broad array of proteomic, phosphoproteomic, transcriptomic, and metabolomic adaptations, including an increase in lysosome production, all occurring without lethality. We found that Arg or Leu starvation induces reversible cell cycle exit, promoting a quiescent state that enhances resistance to cytotoxic stressors. In contrast, cysteine (Cys) and threonine (Thr) deprivation led to cell death via distinct pathways: ferroptosis for Cys starvation, whereas Thr deprivation triggered a previously uncharacterized form of cell death, which could be entirely suppressed by methionine (Met) co-starvation, and mTOR or translational inhibition. These findings suggest that ES cells implement specialized survival strategies in response to different AA limitations, highlighting their ability to reprogram cellular biochemistry under nutrient stress.

DOI: https://doi.org/10.26508/lsa.202503324
EMBO Mol Med. 2025 Aug 29.

Pyrin inflammasome-driven erosive arthritis caused by unprenylated RHO GTPase signaling.

Murali K Akula, Elisabeth Gilis, Pieter Hertens, Lieselotte Vande Walle, Mozes Sze, Julie Coudenys, Yunus Incik, Omar Khan, Martin O Bergo, Dirk Elewaut, Andy Wullaert, Mohamed Lamkanfi, Geert van Loo.

  Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, serves as the substrate for protein geranylgeranylation, a process catalyzed by geranylgeranyl transferase I (GGTase-I). Myeloid-specific deletion of Pggt1b, the gene coding for GGTase-I, leads to spontaneous and severe erosive arthritis in mice; however, the underlying mechanisms remained unclear. In this study, we demonstrate that arthritis in mice with myeloid-specific Pggt1b deficiency is driven by unprenylated GTP-bound small RHO family GTPases, which in turn trigger Pyrin (Mefv) inflammasome activation, GSDMD-dependent macrophage pyroptosis, and IL-1β secretion. We show that although Pggt1b deficiency leads to hyperactivation of RAC1, impaired prenylation alters its proper membrane localization and interaction with effectors, rendering it effectively inactive in vivo. Consequently, unprenylated RHO family signaling promotes Pyrin inflammasome assembly through recruitment to the RAC1 effector IQGAP1. Together, these findings identify a novel inflammatory axis in which non-prenylated RHO GTPase activity promotes spontaneous Pyrin inflammasome activation, pyroptosis, and IL-1β release in macrophages, contributing to inflammatory arthritis in mice.

Keywords:  Arthritis; Prenylation; Pyrin Inflammasome; Pyroptosis; RHO Family GTPases

DOI:  https://doi.org/10.1038/s44321-025-00298-0
Eur J Immunol. 2025 Sep;55(9): e70044

STING and Nonnecroptotic MLKL-Mediated Mechanisms Improve Dendritic Cell Maturation and Killing of Cancer Cells.

Trine S Jensen, Marlene F Laursen, Lea Schort, Agnieszka J Banasik, Ralf Agger, Martin R Jakobsen, Emil Kofod-Olsen.

  Activation of the cGAS-STING pathway plays an important role in antitumor immunity through maturation of tumor-infiltrating DCs. DCs engulf extracellular DNA released by dying cancer cells, supporting activation of the cGAS-STING pathway and concomitant DC maturation. Extracellular DNA in the tumor microenvironment is primarily derived from cells undergoing uncontrolled necrosis or programmed inflammatory death, such as necroptosis, which can be induced when apoptosis pathways are inhibited. Here, we report that caspase inhibition primes activation of a RIPK1/3, MLKL, and STING signaling axis in DCs, resulting in maturation without the need for any further maturation stimuli such as LPS or TNF-α. Notably, these signaling events do not induce DC death, indicating a nonnecroptotic role of the RIPK1-RIPK3-MLKL pathway and novel crosstalk with the STING pathway. Caspase inhibition in DC/cancer cell co-cultures results in DC maturation, inducing TNF-α secretion, which delivers the co-signal to induce cancer cell necroptosis. In summary, we find a collaborative mechanism of the STING and necroptosis pathway in DC maturation, and that activation of the necroptosis pathway has opposite effects on cancer cells and DCs, proposing a possibility for new targets in cancer immunotherapy.

Keywords:  MLKL; STING; caspases; dendritic cells; necroptosis

DOI:  https://doi.org/10.1002/eji.70044
bioRxiv. 2025 Aug 25. pii: 2025.08.20.671346. [Epub ahead of print]

5' cap sequestration is required for sensing of unspliced HIV-1 RNA by MDA5.

Ivy K Hughes, Siarhei Kharytonchyk, Sita Ramaswamy, Sallieu Jalloh, James B Hood, Xianbao He, Andrew J Henderson, Hisashi Akiyama, Alice Telesnitsky, Suryaram Gummuluru.

Heterogenous transcription start site (TSS) usage dictates the structure and function of unspliced HIV-1 RNAs (usRNA). We and others have previously reported that expression and Rev/CRM1-mediated nuclear export of HIV-1 usRNA in macrophages activates MDA5, MAVS, and innate immune signaling cascades. In this study, we reveal that MDA5 sensing of viral usRNA is strictly determined by TSS, 5' leader structure, and RNA function. We show that cap-sequestered HIV-1 usRNAs ( cap 1G) destined for viral genome packaging are specifically targeted by MDA5, while translation-destined ( cap 3G) usRNAs are remarkably immunologically silent. Using mutant viruses which express usRNA with altered 5' cap-exposed leader structure, or inclusion of a retroviral constitutive transport element which drives mRNA-like NXF1-dependent nuclear export of viral usRNA, we show that cap exposure and nuclear export pathway choice are major determinants of both lentiviral RNA immunogenicity and function. In total, we identify innate immune system evasion as a possible rationale for the universal conservation of heterogenous TSS usage among ancestral and extant HIV-1 isolates and shed light on how MDA5 fundamentally discriminates between self and non-self RNAs.
SIGNIFICANCE: Innate immune activation is critical to both the process of initial infection establishment and ongoing chronic inflammation in HIV-1 infection. While MDA5 has been identified as the sensor which detects unspliced HIV-1 RNA produced in infected cells, it remains unclear how HIV-1 unspliced RNAs, which are generated by cellular transcriptional processes, are recognized as non-self. Here, we reveal that HIV-1 RNA function determines MDA5-driven immunogenicity. We show that only unspliced RNAs which traffic to membrane-associated viral assembly sites are immunogenic, while unspliced RNAs which are ribosomally translated to produce viral proteins are immunologically silent. These findings not only advance our knowledge of how the human innate immune system recognizes HIV-1 unspliced RNAs as foreign but also provide a rationale for the selective advantage to generate two pools of unspliced RNAs during HIV-1 replication.

DOI: https://doi.org/10.1101/2025.08.20.671346
Cell Rep. 2025 Sep 03. pii: S2211-1247(25)01011-3. [Epub ahead of print]44(9): 116240

Pp1-87B/PPP1CC-JNK axis integrates apoptosis and ferroptosis-like cell death to regulate cell competition and tumorigenesis.

Du Kong, Zhongbo Li, Sihua Zhao, Xueliang Yang, Jiadong Zheng, Yifan Guo, Wenyan Xu, Han Gao, Hanqing Guo, Qiang Zhang, Jian Zhu, Xianjue Ma, Bin Jin.

  Cell competition, an evolutionarily conserved quality control mechanism, selectively removes unfit or pre-malignant cells via cell-cell interactions. Through a genetic screen in Drosophila, we identify the phosphatase Pp1-87B as an essential regulator of JNK signaling crucial for eliminating scrib-deficient precancerous cells during tumor-suppressive cell competition. Mechanistically, impaired Pp1-87B activates JNK signaling via the Moe-Rho1 axis. Subsequently, JNK signaling acts as a central hub, integrating apoptosis and ferroptosis-like cell death by activating the Hippo signaling pathway. Critically, we demonstrate that the human ortholog, PPP1CC (protein phosphatase 1 catalytic subunit gamma), functions similarly to drive apoptosis and ferroptosis in human liver tumor cells through JNK activation. Collectively, our findings provide insights into the molecular integration of distinct cell death pathways during premalignant cell elimination in cell competition and identify PPP1CC as a promising therapeutic target for liver cancer treatment.

Keywords:  CP: Cancer; Drosophila; Hippo pathway; JNK pathway; PPP1CC; Pp1-87B; TSCC; ferroptosis; liver cancer; scrib; tumor-suppressive cell competition

DOI:  https://doi.org/10.1016/j.celrep.2025.116240