Nideffer J, Bach F, Strubbe S
… +27 more, Lopez L, Zedi M, Nankya F, Briggs J, van der Ploeg K, Musinguzi K, Kim S, Garcia Romero A, Keya A, Camanag K, Lewis S, Abdelbasset M, Wang B, Boss A, Nansubuga E, Nankabirwa JI, Arinaitwe E, Takahashi S, Dorsey G, Greenhouse B, Rodriguez-Barraquer I, Kamya MR, Bacchetta R, Ssewanyana I, Haque A, Roncarolo MG, Jagannathan P
Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell po...Plasmodium falciparum (Pf) induces the clonal expansion of antigen-specific type 1 regulatory T (Tr1) cells capable of long-term memory. Tr1 cells comprise nearly 90% of the Pf blood stage antigen-specific CD4+ T cell pool in children. Though, whether Tr1 cells contribute to protection from malaria remains undetermined. To address this critical knowledge gap, we first performed scRNA-seq on gated cell populations and validated CXCR6+ CD127- as new phenotypic markers to enrich for bona-fide Tr1 cells. Importantly, these Tr1 cells potently suppressed the proliferation of other CD4+ T cells in vitro via IL-10 secretion. Among children living in malaria-endemic Uganda, CXCR6+ CD127- Tr1 cells were the dominant responding subset to Pf-infected red blood cell stimulation in vitro. They also rapidly expanded following malaria and expressed IL-10 and IFNγ during infection in vivo. Tr1 abundance correlated with plasma concentrations of granzyme A, IFNγ, IL-10, and LAG3, suggesting that these cells act systemically. Higher CXCR6+ CD127- Tr1 cell frequencies correlated with a lower probability of symptoms given parasitemia but were also associated with delayed parasite clearance among untreated, asymptomatic children. These data suggest that Tr1 cells help mediate clinical immunity to malaria but may also facilitate parasite persistence through mechanisms of immune regulation.
Brown RJ, Khan MT, Houston AJ
… +5 more, Niu H, Podojil JR, Choy B, Cui W, Meeks JJ
J Clin Invest
· 2026 Jun · PMID 42081487
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BACKGROUNDPrimary therapy for high-risk bladder cancer (BCa) is repeated instillations of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG). Although BCG reduces the risk of recurrence by more than half, the mechan...BACKGROUNDPrimary therapy for high-risk bladder cancer (BCa) is repeated instillations of the tuberculosis vaccine Bacillus Calmette-Guérin (BCG). Although BCG reduces the risk of recurrence by more than half, the mechanisms underlying its immune-activating effects remain unknown. Our objective was to investigate how the immune response differs between BCG responders and nonresponders and to compare systemic and local immune responses.METHODSWe performed scRNA-seq of isolated immune cells adjacent to high-risk bladders in BCG responders and nonresponders before and after BCG. We also compared concurrent scRNA-seq profiles of circulating immune cell populations with those of bladder immune cells.RESULTSWe observed an increase in Th17-like Th1 cells in BCG responders, characterized by greater expression of proinflammatory cytokines. By contrast, nonresponders showed increased CD8+ T cell exhaustion and Treg cells. We found that the primary mechanism driving divergent T cell activity is altered polarization and immunosuppressive signaling with myeloid cells. Using a machine learning-based approach, we identified that Th17-like Th1 cytokines, such as IL-17, IL-21, and IL-26, are predictive of response, which was subsequently validated in a separate BCG-treated BCa cohort.CONCLUSIONTogether, these findings suggest that dynamic regulation of myeloid-T cell interactions can be critical for outcomes of BCG-treated BCa.FUNDINGBX005599 and BX003692 (Veterans Health Administration), HT94252410507 (Department of Defense), R01CA298333 (National Cancer Institute), and Robert H. Lurie Comprehensive Cancer Center H Foundation Core Facility Pilot Project Award.
Rosas IO, McDowell-Sanchez AK, Sanchez S
… +11 more, Cala-Garcia JD, Waich Cohen AR, Ruiz-Echartea E, Ochsner SA, Kraushaar DC, Celada LJ, Sun D, Polverino F, Coarfa C, McKenna NJ, Tsoyi K
J Clin Invest
· 2026 Jun · PMID 42066052
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Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular env...Idiopathic pulmonary fibrosis (IPF) is a devastating chronic lung disorder with limited treatment options. Macropinocytosis is one of the key cellular processes involved in nutrient consumption from the extracellular environment under stress conditions. Here, we studied the role of macropinocytosis in experimental pulmonary fibrosis models. We found that macropinocytosis is increased in human lung fibroblasts (HLFs) derived from patients with IPF. The inhibition of macropinocytosis with 5-(n-ethyl-n-isopropyl)-amiloride (EIPA) inhibited profibrotic responses in IPF-derived and TGF-β1-stimulated HLFs and reduced pulmonary fibrosis in bleomycin-injured (Bleo-injured) mice. EIPA exerted its antifibrotic effects by regulating amino acid uptake, mammalian target of rapamycin complex 1 (mTORC1) activation and mesenchyme homeobox1 (MEOX1) expression in activated HLFs. Fittingly, genetic inhibition of macropinocytosis also ameliorated lung fibroblast activation and pulmonary fibrosis in mice. Using IPF-derived precision cut lung slices (PCLSs), we observed robust repression of profibrotic gene expression programs in EIPA-treated PCLSs across different fibroblast subpopulations. Finally, we found that imipramine (Imi), a tricyclic antidepressant approved by the FDA, effectively inhibited macropinocytosis and ameliorated profibrotic responses in lung fibroblasts, Bleo-injured mice, and IPF-derived PCLSs. Taken together, our results suggest that macropinocytosis inhibition can be considered as a potential therapeutic strategy to treat pulmonary fibrosis.
Xu H, Van der Jeught K, Zhou Z
… +20 more, Zhang L, Yu T, Sun Y, Li Y, Wan C, So KM, Liu D, Frieden M, Fang Y, Mosley AL, He X, Zhang X, Sandusky GE, Liu Y, Meroueh SO, Zhang C, Wijeratne AB, Huang C, Ji G, Lu X
J Clin Invest
· 2026 May · PMID 42065250
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Gherardini J, Samra T, Gomez-Gomez T
… +13 more, Akhundlu A, Verling SD, Linowiecka K, Wikramanayake TC, Knie U, Rodríguez-Feliz J, Kassir R, Funk W, Azar RP, Annis DA, Aivado M, Chéret J, Paus R
J Clin Invest
· 2026 May · PMID 42065249
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Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Yet, no therapy is available to selectively protect healthy hair follicles (HFs) and their epithelial stem cells...Chemotherapy-induced alopecia (CIA) remains one of the most distressing adverse effects of cancer therapy. Yet, no therapy is available to selectively protect healthy hair follicles (HFs) and their epithelial stem cells (eHFSCs) from chemotherapy-induced damage without awarding potential survival benefits to cancer cells. Here, we report how human HFs can be protected against 2 lead CIA-inducing chemotherapeutics by inducing selective transient cell cycle arrest. Pretreating scalp HFs before chemotherapy exposure ex vivo with ALRN-6924, a clinical-stage "stapled peptide" drug that binds with high affinity to key endogenous inhibitors of p53, selectively activated p53 signaling only in cells with wild-type TP53 genotype and upregulated p21. This led to temporary cell cycle arrest in healthy tissues without protecting TP53-mutant cancer cells and mitigated chemotherapy-induced HF damage on multiple levels, including excessive hair matrix apoptosis, premature catagen, pigmentary abnormalities, "mitotic catastrophe," and micronucleation. It also protected eHFSCs against DNA damage, apoptosis, and pathological epithelial-mesenchymal transition. Notably, even topically applied ALRN-6924 afforded relative chemotherapy protection ex vivo. These results provide proof of principle for a strategy to selectively protect rapidly proliferating healthy epithelial tissues and their stem cells in patients with TP53-mutant cancers, which promises to protect against acute and permanent CIA.
Lopez-Janeiro A, González-Gomariz J, Issa F
… +20 more, Hester J, Porciuncula A, Teijeira A, Luri-Rey C, Ruiz-Guillamon D, Perez-Gracia JL, Perez-Ruiz E, Barragan I, Martín-Algarra S, Sanmamed MF, Ortego I, Rodriguez-Ruiz ME, Alexandru R, Rodriguez I, Arrieta-Aranzueque S, Rimm D, Aung T, Schalper KA, de Andrea CE, Melero I
J Clin Invest
· 2026 May · PMID 42065248
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Conventional type-1 dendritic cells (cDC1) are the main mediators of crosspresentation of tumor antigens to CD8+ T cells and provide a context of costimulatory molecules and cytokines that lead to cytotoxic T lymphocyte...Conventional type-1 dendritic cells (cDC1) are the main mediators of crosspresentation of tumor antigens to CD8+ T cells and provide a context of costimulatory molecules and cytokines that lead to cytotoxic T lymphocyte (CTL) responses. We analyzed bulk RNA sequences from 7 key clinical trials testing checkpoint inhibitors across multiple cancer types. cDC1- and CD8-associated gene signatures were analyzed. Multiplex tissue immunofluorescence was used to quantify cDC1 in melanoma, urothelial cancer, and non-small-cell lung cancer (NSCLC) samples and assess cDC1 tissue neighborhoods. Melanoma samples were studied with Xenium spatial transcriptomics (ST) and one series of NSCLC was analyzed using GeoMX-DSP. Strong associations across tumor types were found between cDC1 and CD8+ T cell transcripts with clinical outcomes. As mechanistically expected, transcripts for the CCL4 and CCL5 chemokines and the growth factor FLT3-L showed associations with cDC1 abundance. Tissue immunofluorescence showed a strong correlation of cDC1 and CD8+ T cell infiltration with clinical benefit upon treatment with checkpoint inhibitors (CPIs). Moreover, short distance between cDC1 and CD8+ T cells was found to define tissue niches associated with favorable outcomes. ST revealed recent T cell activation within immune cDC1-rich niches. cDC1 abundance, which determines CD8+ T lymphocyte density and activation in tumor tissues across cancer types, is strongly associated with clinical response to CPI-based immunotherapies.
Wang P, You N, Teng YS
… +17 more, Lv YP, Tian WQ, Xu JY, Xie R, Wu JB, Yue GY, Cheng P, Zhang JY, Peng LS, Mao FY, Luo SL, Yang SM, Zhao YL, Zhou H, Chen W, Wang B, Zhuang Y
J Clin Invest
· 2026 May · PMID 42065246
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Bacteria-modulated gastric epithelial cells (GECs) play key roles in Helicobacter pylori-associated pathology. Here, we demonstrate both procolonization and proinflammation roles of GEC-derived PPFIA4 in H. pylori infect...Bacteria-modulated gastric epithelial cells (GECs) play key roles in Helicobacter pylori-associated pathology. Here, we demonstrate both procolonization and proinflammation roles of GEC-derived PPFIA4 in H. pylori infection. PPFIA4 was elevated in GECs from gastric mucosa of H. pylori-infected patients and mice. PPFIA4 could be synergistically induced by H. pylori and IL-33 via the CagA/AP1 pathway. Human gastric PPFIA4 correlated with H. pylori colonization and the severity of gastritis, and H. pylori colonization and inflammation were attenuated in Ppfia4ΔGEC mice. Mechanistically, PPFIA4's SAM1 domain bound domains from CaMK to the first L27 of CASK and subsequently formed a PPFIA4/CASK/AKT1 complex to activate AKT1, resulting in NF-κB activation and MMP1/CXCL3 secretion. This not only led to decreased E-cadherin and ZO-1 by MMP1, thereby promoting gastric mucosal damage to foster H. pylori colonization, but also resulted in increased gastric influx of G-MDSCs via CXCL3-dependent migration, thereby promoting gastritis and impairing H. pylori-specific IFN-γ-producing CD4+ T cell responses to foster H. pylori colonization. Furthermore, we identified a PPFIA4 inhibitor, kira6, which effectively inhibited GEC's MMP1/CXCL3 production and ameliorated gastric H. pylori colonization and gastritis. Overall, PPFIA4 could be a promising therapeutic target, as it collectively ensures H. pylori persistence and promotes gastritis.
J Clin Invest
· 2026 May · PMID 42065244
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The immune response is essential for maintaining host integrity, and phagocytosis is widely considered as one of its most ancient cellular functions. Accordingly, professional phagocytes such as resident tissue macrophag...The immune response is essential for maintaining host integrity, and phagocytosis is widely considered as one of its most ancient cellular functions. Accordingly, professional phagocytes such as resident tissue macrophages (RTMs) populate virtually all organs and serve as primary sentinels capable of sensing, engulfing, and eliminating invading pathogens. Yet, reflecting their early evolutionary emergence, RTMs have acquired functions that extend far beyond phagocytosis. In this issue, Salm et al. extend the macrophage toolbox, showing that macrophages residing in the peritoneal cavity function as remote healers. Using various mouse models, they demonstrated that activated peritoneal macrophages accelerate distant skin wound healing through fibronectin secretion, thereby shaping tissue repair at sites beyond their anatomical location. These findings invite us to reconsider macrophages not only as phagocytes and mediators of inflammation but also as active regulators capable of shaping extracellular architecture at a distance.
J Clin Invest
· 2026 May · PMID 42065243
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Although combination antiretroviral therapy (ART) has dramatically reduced the incidence of severe HIV-associated neurological disease, the central nervous system (CNS) remains a viral sanctuary in which inflammation and...Although combination antiretroviral therapy (ART) has dramatically reduced the incidence of severe HIV-associated neurological disease, the central nervous system (CNS) remains a viral sanctuary in which inflammation and brain injury persist despite systemic viral suppression. Here, we synthesize evidence that ongoing HIV-associated brain injury is sustained not primarily by unchecked viral replication but by persistent viral transcription from defective proviruses, immune-mediated synaptic dysfunction driven by bystander activation, and long-lived microglial reprogramming shaped by epigenetic "training." We highlight how emerging single-cell multiomics and "liquid biopsy" approaches are redefining our understanding of the CNS reservoir at high resolution. We further discuss the growing emphasis on biologically anchored, molecularly defined disease subtypes as a means to disentangle HIV-specific pathology from the confounding overlap of aging and multimorbidity, which have increased in the ART era. Finally, we underscore the necessity of human-centered translational studies to validate preclinical findings, outlining how these molecular insights pave the way for precision therapeutics and CNS-targeted cure strategies.
Xing W, Zhou Y, Haedicke K
… +12 more, Wang C, Vazquez-Prada KX, Wu H, Lin Z, Andreou C, Zhang Q, Shang K, Hu R, Kircher M, Ye X, Grimm J, Yang J
J Clin Invest
· 2026 May · PMID 42065242
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Integrative multiscale imaging bridges the gap between macroscopic organ structures and microscopic cellular processes, enabling holistic visualization of anatomy and function across scales. Photoacoustic imaging (PAI) l...Integrative multiscale imaging bridges the gap between macroscopic organ structures and microscopic cellular processes, enabling holistic visualization of anatomy and function across scales. Photoacoustic imaging (PAI) leverages melanin's potent contrast for label-free melanoma detection, yet its potential in lung imaging, challenged by air-tissue acoustic impedance mismatch, remains unexplored for melanoma lung metastases (MLMs). We used hierarchical multiscale PAI, transitioning from whole-body macroscale to localized mesoscale and single-cell-resolution microscale. PAI also guided photoablation interventions in the first and second near-infrared windows, requiring only 10.4 pg intracellular melanin/cell. Bioinformatic analysis of human MLM tissues revealed perturbed signaling pathways compared with normal skin and lung tissues, accounting for dysfunctional melanogenesis to enable label-free PAI with high sensitivity and specificity. Malignant MLM lesions in living mice, resected mouse lungs, and human lungs were delineated with margins closely conforming to histology. The high sensitivity allowed visualization of low-cellularity microsatellite foci down to a few tens of cell clusters, with sufficient penetration in the lungs of mice and Bama minipigs. The multiscale imaging methodology streamlines a theranostic workflow and specifically identifies MLM burden in a progressive, label-free manner, which may aid real-time tumor ablation in the future.
J Clin Invest
· 2026 May · PMID 42065241
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Chemotherapy-induced alopecia (CIA) is a common and highly visible adverse effect of chemotherapy with substantial psychosocial and quality-of-life burdens. In this issue, Gherardini and colleagues described a targeted s...Chemotherapy-induced alopecia (CIA) is a common and highly visible adverse effect of chemotherapy with substantial psychosocial and quality-of-life burdens. In this issue, Gherardini and colleagues described a targeted strategy to prevent CIA using ALRN-6924, a stapled peptide that transiently activates p53 and induces cell cycle arrest in proliferating TP53 wild-type tissues, such as the hair follicle. In ex vivo human scalp hair follicle culture, ALRN-6924 protected matrix keratinocytes and bulge stem cells from paclitaxel- and cyclophosphamide-induced injury, reducing apoptosis, DNA damage, and other pathologic features. These findings nominate precision chemoprotection as a promising supportive care approach for mitigating CIA.
Qiu X, Lu Y, Tang Y
… +10 more, Zhou L, Lee YT, Meng Z, Chen Z, Pradeepa F, Faccioli LA, Hu Z, Soto-Gutierrez A, Li S, Lin JD
J Clin Invest
· 2026 May · PMID 42065240
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Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of...Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus-mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.
J Clin Invest
· 2026 May · PMID 42065239
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Fatty acid oxidation (FAO) provides the healthy heart with 60%-90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fue...Fatty acid oxidation (FAO) provides the healthy heart with 60%-90% of its ATP, with the remainder coming from metabolism of glucose. Metabolic flexibility is key to heart function, ensuring an uninterrupted source of fuel. In heart failure, a shift from FAO to glucose-dependent metabolism occurs as disease progresses, supporting the widely held notion that fat is the optimal substrate in the heart. In this issue of the JCI, Kim et al. challenge this assumption. In studies of acetyl-CoA carboxylase-deficient (ACC-deficient) mice, they found that unregulated use of fat as a substrate led to cardiac damage. ACC-deficient mice developed cardiolipin deficiency as a result of excessive FAO depleting stores of linoleic acid, which is used as a substrate for cardiolipin maturation. The resulting mitochondrial dysfunction was associated with dilated cardiomyopathy and heart failure in these mice. The findings highlight potential for development of therapeutic strategies that balance energy sources and replenish cardiolipin levels.
Kim CW, Vale G, Fu X
… +11 more, McDonald JG, Dai C, Li C, Wang ZV, Sharma G, Khemtong C, Malloy CR, Deja S, Burgess SC, Mitsche MA, Horton JD
J Clin Invest
· 2026 May · PMID 42065238
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Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utiliza...Cardiomyocytes primarily rely on fatty acid oxidation (FAO), which provides more than 70% of their energy. However, excessive FAO can disrupt cardiac metabolism by increasing oxygen demand and suppressing glucose utilization through the Randle cycle. Although inhibition of FAO has been investigated in heart failure, its overall therapeutic impact remains uncertain. To determine the consequences of enhanced FAO, we generated cardiomyocyte-specific ACC1 and ACC2 double-knockout (ACC dHKO) mice, which exhibit constitutively elevated FAO. ACC dHKO mice developed dilated cardiomyopathy and heart failure. Lipidomic analysis revealed marked depletion of cardiolipin caused by reduced linoleic acid, a direct consequence of excessive FAO. This cardiolipin deficiency impaired mitochondrial electron transport chain (ETC) activity, leading to mitochondrial dysfunction. Pharmacologic inhibition of FAO with etomoxir or oxfenicine restored cardiolipin levels, normalized ETC activity, and prevented cardiac dysfunction in ACC dHKO mice. These findings demonstrate that unrestrained FAO disrupts both lipid and energy homeostasis, culminating in heart failure in this model. Collectively, these results indicate that although FAO is essential for cardiac energy production, therapeutic strategies aimed at stimulating cardiac FAO may be detrimental rather than beneficial in heart failure.
Zaidi M, Kim SM, Ryu V
… +5 more, Lizneva D, Davies TF, Rosen CJ, Yuen T, Giustina A
J Clin Invest
· 2026 May · PMID 42065237
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Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteo...Bone is a highly dynamic and purposefully organized structure that remodels constantly throughout adult life. Disordered bone remodeling, in which resorption of old bone by osteoclasts exceeds new bone formation by osteoblasts, results in bone loss, which, in turn, is associated with debilitating conditions, including osteoporosis and metastatic bone disease. The past decade has revealed vital new insights into the role of the central nervous system in skeletal regulation. These studies have led to a better understanding of physiologic circuitry, enabled us to revisit disease pathophysiology, and in doing so, prompted the creation of candidate therapeutics. The central neural control of bone is exerted through two arms - an amplitude-modulated (AM) neurohormonal arm that relies on changes in circulating levels of anterior and posterior pituitary hormones, which act on bone directly, and a frequency-modulated (FM) arm that arises from changes in the firing frequency of sympathetic, parasympathetic, and sensory nerves that innervate bone. Here, we review the medical consequences arising from the dysfunction of the AM and FM arms, as well as studies that have unmasked promising therapeutic targets.
J Clin Invest
· 2026 May · PMID 42065236
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Despite extensive advances in understanding sepsis pathophysiology, treatment outcomes have not substantially improved. In this issue, Takahama and colleagues identified phospholipase A2 Group V (PLA2G5) as a contributor...Despite extensive advances in understanding sepsis pathophysiology, treatment outcomes have not substantially improved. In this issue, Takahama and colleagues identified phospholipase A2 Group V (PLA2G5) as a contributor to sepsis lethality in mouse models of endotoxemia and sepsis. Whole-mouse spatial profiling generated bodywide maps of systemic inflammation and uncovered intestinal goblet cells as a source of pathogenic PLA2G5. Pairs of inflammatory cytokines (TNF and IFN-γ, or TNF and IL-18) induced PLA2G5 expression in goblet cells. Mechanistically, circulating PLA2G5 triggered intravascular hemolysis through its lipolytic activity on erythrocyte membranes and contributed to organ failure and death. PLA2G5's deleterious effects were blocked by specific antibodies and were absent in Pla2g5-deficient mice. In humans with bacterial or fungal sepsis or severe COVID-19, plasma PLA2G5 levels were elevated and predicted disease severity. This discovery highlights the contribution of hemolysis to sepsis, suggesting that PLA2G5 inhibitors, hemoglobin, or heme antagonists could represent valuable therapeutic tools.