Shenoy SK, Gutay M, Brown I
… +11 more, Rogers TD, Banner K, Olegario N, Griffin N, Goodell HP, Yoder B, Lalush DS, Edwards DA, Boucher RC, Grubb BR, Button B
J Clin Invest
· 2026 May · PMID 41843010
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Airway mucus clearance from the lungs occurs by 2 widely recognized mechanisms: cilia-mediated clearance and high-velocity airflow-mediated cough clearance. However, a potentially important third mechanism of mucus clear...Airway mucus clearance from the lungs occurs by 2 widely recognized mechanisms: cilia-mediated clearance and high-velocity airflow-mediated cough clearance. However, a potentially important third mechanism of mucus clearance, referred to as cilia-independent gas-liquid transport (GLT), was proposed based on in vitro model systems to occur during normal tidal breathing but has largely been overlooked. We conducted in vitro and in vivo studies to investigate the role of tidal breathing airflow rates in mucus clearance. An in vitro airway culture bead-tracking model demonstrated airflow-dependent mucus transport at tidal breathing flow rates. As with other modes of mucus clearance, GLT was critically dependent on mucus concentration. In vivo studies in cilial beat-deficient mice demonstrated that GLT-mediated mucus clearance occurs during tidal breathing in the absence of cough, and the rate of GLT mucus clearance was dependent on breathing frequency and body orientation. These studies demonstrated that GLT is a third mechanism of mucus clearance and likely represents a significant mode of clearance in persons with cilial dysfunction. These findings indicate that increasing breathing rates through exercise, using mucus rehydrating agents or mucolytics, or combining these approaches may restore clinically and physiologically meaningful airway clearance in these patients.
Gan C, Lai E, Tai Y
… +20 more, Chen S, Zhao C, Dai W, Yang Z, Li B, Lan T, Xiao Y, Guo Y, Chen J, Wei B, Che Z, Cao S, Liu M, Tacke F, Tang C, Shah VH, Yu H, Wang F, Huang Z, Gao J
J Clin Invest
· 2026 Jun · PMID 41842990
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Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell r...Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4-dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation-dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
Christensen BA, Tat J, Leonard MZ
… +13 more, Emerson SD, Roberts S, Holmgren EB, Konomi-Pilkati A, Reiley HB, Gomez DM, Zheng L, Yoon HJ, Lago SH, Carr AL, Brady LJ, Chevée M, Calipari ES
J Clin Invest
· 2026 May · PMID 41842974
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Stimulant medications are widely prescribed for attention deficit hyperactivity disorder (ADHD) and have significant abuse liability. Here, we show that, consistent with clinical data, female mice exhibited enhanced beha...Stimulant medications are widely prescribed for attention deficit hyperactivity disorder (ADHD) and have significant abuse liability. Here, we show that, consistent with clinical data, female mice exhibited enhanced behavioral sensitivity to stimulants, and we define sex- and hormone-dependent adaptations in the dopamine system that contributed to these effects. Single-nucleus RNA-seq of ventral tegmental area dopamine neurons revealed that projections to the nucleus accumbens (NAc) core, compared with other projection populations, were a hub of sexually dimorphic gene expression, including transcripts regulating dopamine synthesis, and transport. These molecular differences coincided with enhanced dopamine release and clearance in female mice, particularly during phases of the estrous cycle when estradiol levels were high. The stimulants amphetamine (a releaser) and methylphenidate (a reuptake inhibitor) more effectively increased dopamine levels in female mice under certain conditions. However, amphetamine showed more robust hormone-sensitive regulation, with potency reduced by ovariectomy and restored by direct estradiol replacement in the NAc core. Together, the findings indicate that even within a drug class, drugs with different mechanisms of action can leverage different aspects of sexually dimorphic dopamine function. This distinction highlights the notion that sex differences are not uniform but can be differentially sensitive to drug pharmacology.
Gu W, Wang X, Solmonson A
… +20 more, Cai L, Xiao Y, Tasdogan A, Franklin J, Zhang Y, Zhang H, Westfall AK, Rowe A, Trivedi H, Faubert B, Wu Z, Sudderth J, Zacharias LG, Afroze B, Bezprozvanny I, Sudarshan S, Cai F, McBrayer SK, Mathews TP, DeBerardinis RJ
J Clin Invest
· 2026 May · PMID 41842973
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High levels of l- and d-2-hydroxyglutarate (2HG), the reduced forms of α-ketoglutarate (αKG), are implicated in neurodevelopmental disorders and cancer by modulating αKG-dependent dioxygenases involved in histone, DNA, a...High levels of l- and d-2-hydroxyglutarate (2HG), the reduced forms of α-ketoglutarate (αKG), are implicated in neurodevelopmental disorders and cancer by modulating αKG-dependent dioxygenases involved in histone, DNA, and RNA demethylation. L-2HG dehydrogenase (L2HGDH) deficiency, a rare autosomal recessive inborn error of metabolism associated with systemic L-2HG elevation, causes progressive neurological disability and increased brain tumor risk of unclear mechanism. Using an isogenic, patient-derived induced pluripotent stem cell system, we examined the impact of L2HGDH deficiency on neural progenitor cell (NPC) function and neuronal differentiation. L2HGDH deficiency caused L-2HG accumulation, NPC hyperproliferation, increased clonogenicity, and defective neuronal differentiation in 2D cultures and cortical spheroids. Editing the L2HGDH locus to WT reversed these effects. Inhibiting glutaminase reduced L-2HG levels and induced neuronal differentiation. L-2HG-dependent inhibition of KDM5 histone demethylases led to widespread retention of H3K4me2/3, markers of active gene expression, with prominent enrichment at the MYC locus and elevated MYC expression across multiple neural cell types. Despite broadly altered histone methylation, genetically or pharmacologically normalizing MYC completely restored neuronal differentiation. These data indicated that a primary metabolic disturbance activated MYC to favor self-renewal and suppress neuronal lineage commitment.
Yang Y, Zhang X, Venkadakrishnan VB
… +15 more, Zou H, Zheng X, Guo S, Chen CZ, Borowsky AD, Corey E, Evans RM, Gao AC, Dall'Era MA, Zoubeidi A, Lara PN, Kung HJ, Chen X, Beltran H, Chen HW
J Clin Invest
· 2026 May · PMID 41842971
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PRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for the treatment of advanced cancers including metastatic prostate cancer. Here, we show that PRC2i/EZH2i alone or in combination with androgen receptor (AR) inhibitors i...PRC2/EZH2 inhibitors (PRC2i/EZH2i) are promising for the treatment of advanced cancers including metastatic prostate cancer. Here, we show that PRC2i/EZH2i alone or in combination with androgen receptor (AR) inhibitors induced diverse cell state programs (CSPs) (e.g., response to stress or IFN, MYC targets, stem cells, EMT lineage plasticity, and multiple developmental programs), which led to increased tumor cell invasion, metastasis, and resistance to other drugs, in addition to modest suppression of tumor growth. In contrast to the current perception, our comprehensive, integrated genomics and epigenomics profiling of patient-derived xenografts (PDXs) and clinical tumors revealed that PRC2/EZH2 suppressed CSP genes by maintaining chromatin bivalency. Hyperactive Wnt/β-catenin signaling and inhibitors of polycomb-repressive complex 2/enhancer of zeste homolog 2 (PRC2/EZH2) and the AR alter chromatin bivalency through antagonism of PRC2 and stimulation of MLL2/KMT2B in a feed-forward manner. The circadian rhythm regulator REV-ERBα unexpectedly reprogrammed β-catenin in promoting bivalency resolution and CSP gene expression. Dual targeting of Wnt/β-catenin and EZH2 diminished diverse cell states by restoring bivalency and effectively blocked tumor growth. Our findings provide unexpected insights into chromatin bivalency and dysregulated circadian rhythms in the control of cell state diversity and identify alternative therapeutic strategies that target PRC2/EZH2 for advanced malignancies.
Liu S, Ren Q, Mo G
… +16 more, Li Z, Huang H, Zhou Y, Miao Z, Cao X, Wu B, Xiao Z, Yu S, Wu G, Xia L, Cui J, Mo J, Li Y, Xia L, Shen J, Xiao S
J Clin Invest
· 2026 May · PMID 41842966
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Despite substantial progress in understanding the molecular pathology of Parkinson's disease (PD), the underlying drivers of PD in many cases remain unknown. Here, we investigate the role of RNA modification in PD, follo...Despite substantial progress in understanding the molecular pathology of Parkinson's disease (PD), the underlying drivers of PD in many cases remain unknown. Here, we investigate the role of RNA modification in PD, following observations of selective m6A hypomethylation in the substantia nigra (SN) of mouse PD models and dysregulated METTL3 and ALKBH5 expression in dopaminergic (DA) neurons from patients with PD. We found preferential m6A deposition on transcripts of PD risk genes and what we believe to be a previously unreported heterozygous METTL3 p.K480R mutation in patients with PD. Mettl3K480R/+ mice exhibited progressive METTL3 reduction and m6A hypomethylation in the SN, leading to progressive DA neuron loss, phospho-α-synuclein increase, and levodopa-responsive motor and nonmotor deficits, mimicking PD progression. Dopamine transporter-specific METTL3 knockout mice recapitulate m6A hypomethylation, neurodegeneration, and levodopa-responsive parkinsonism. Mechanistically, m6A deficiency disrupted mitochondrial biogenesis and function through regulating Tfam expression, while mitochondrial dysfunction reciprocally impaired m6A deposition, creating a pathogenic loop. Importantly, supplementation with S-adenosylmethionine (SAMe) enhanced m6A modification, disrupted the pathogenic loop, and alleviated parkinsonism in mouse models. Our findings revealed m6A dysregulation as an important contributor to PD pathogenesis, provide a valuable preclinical mouse model for PD progression, and highlight RNA methylation-targeted therapies as a promising strategy for PD intervention.
J Clin Invest
· 2026 May · PMID 41842961
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Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key...Glioblastoma (GBM) is a highly aggressive brain tumor characterized by extensive crosstalk between glioblastoma stem cells (GSCs) and immunosuppressive microglia, with our previous work identifying CLOCK and TFPI2 as key regulators of this interaction. Here, we uncover a 'symbiotic exclusivity' pattern between CLOCK and TFPI2, showing that, despite mutually exclusive amplifications, they sustain symbiotic regulatory interactions in GBM. The CLOCK-BMAL1 complex transcriptionally upregulates TFPI2, while TFPI2-driven hypoxia inducible factor 1 α (HIF-1α) signaling activates nuclear factor k B (NF-kB) P65 to upregulate the CLOCK-BMAL1 complex, creating a positive feedback loop to promote stemness, immunosuppression, and tumor progression. Disrupting the CLOCK-TFPI2 interplay through dual inhibition of their downstream effectors reduces GSC stemness and immunosuppressive microglia, activates antitumor immunity, and synergizes with anti-PD1 therapy to achieve complete tumor regression in 50%-62.5% of tumor-bearing mice. This study uncovers a promising therapeutic strategy for a broader subset of patients with GBM with high expression of either CLOCK or TFPI2, and provides a framework for identifying 'symbiotic exclusivity' genes in cancer.
Li X, Song Z, Lin S
… +7 more, Luo M, Liu S, Liu Y, Zhang F, Xu L, Liu C, Zhang H
J Clin Invest
· 2026 May · PMID 41842958
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Gemcitabine-based chemotherapy is the standard treatment regimen for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehyd...Gemcitabine-based chemotherapy is the standard treatment regimen for advanced intrahepatic cholangiocarcinoma (iCCA), but the frequent presence of chemoresistance limits its efficacy. Here, we identified isocitrate dehydrogenase 1 (IDH1) as the crucial target that confers chemoresistance of iCCA to gemcitabine using a druggable CRISPR/Cas9 library. The positive association between IDH1 expression and chemoresistance was revealed in a gemcitabine-treated iCCA cohort and with cell-based drug sensitivity assays. Utilizing patient-derived organoids, cell line-derived xenografts, and patient-derived xenografts, we demonstrated that IDH1 knockdown or IDH1 pharmacological inhibition facilitated gemcitabine efficacy in these preclinical iCCA models carrying wild-type IDH1 (wtIDH1). Mechanistically, wtIDH1 oxidizes isocitrate to generate α-ketoglutarate and NNADPH, thereby creating a mechanism to manage the oxidative stress induced by gemcitabine, maintaining cellular redox homeostasis, and, ultimately, leading to chemoresistance to gemcitabine. Significantly, ivosidenib, the FDA-approved allosteric IDH1 inhibitor, demonstrated synergistic antitumor efficacy with gemcitabine in wtIDH1 preclinical iCCA models through boosting intracellular oxidative stress under physiological conditions. The low level of Mg2+, an ion that competitively hinders binding of ivosidenib on wtIDH1, in the iCCA tumor microenvironment contributed to the expanded therapeutic window for use of ivosidenib in patients with iCCA. Our work revealed the potency of combining targeting IDH1 and chemotherapy against wtIDH1 iCCA and other tumors.
Harvey ME, Shi M, Oh Y
… +7 more, Page TM, Mitchell DA, Luo A, Slayden OD, MacLean JA, Sharma A, Hayashi K
J Clin Invest
· 2026 May · PMID 41842953
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This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple lesion induction mouse model (MIM), as repeated retrograde menstruation is consid...This study investigated how chronic pelvic pain (CPP) develops using rhesus macaques with naturally occurring endometriosis and a multiple lesion induction mouse model (MIM), as repeated retrograde menstruation is considered an underlying mechanism of endometriosis pathogenesis. MIM increased lesion numbers and elevated hypersensitivity. Elevated persistent glial cell activation was observed across multiple brain regions or spinal cords in MIM and rhesus macaques. Elevated TRPV1, SP, and CGRP expressions in the dorsal root ganglia (DRG) were persistent in MIM. MIM induced the severe disappearance of TIM4hiMHCIIlo residential macrophages and an influx of increased pro-inflammatory TIM4loMHCIIhi macrophages in the peritoneal cavity. Cytokine levels were persistently elevated in MIM. Furthermore, dienogest (a synthetic progestin) and fingolimod (a selective immunosuppressor) reduced hyperalgesia and neuroinflammation. Our results indicate that recurrent retrograde menstruation can be a peripheral stimulus that induces nociceptive pain and creates a composite chronic inflammatory stimulus, leading to neuroinflammation and sensitization of the central nervous system. The circuits of neuroplasticity and stimulation of peripheral organs via a feedback loop of neuroinflammation may mediate widespread endometriosis-associated CPP. These findings in mice were further supported by results from the spontaneously developed advanced endometriosis in rhesus macaques via recurrent retrograde menstruation.
Zhu Y, Li G, Guo Y
… +10 more, He Y, Zhang W, Gao L, Zhang J, Guo P, Lin H, Zhang W, Wei Z, Xia Y, Dai Y
J Clin Invest
· 2026 May · PMID 41842952
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Understanding susceptibility factors of sepsis is crucial for early diagnosis and development of personalized treatment strategies. However, the genetic determinants for initiation and progression of sepsis remain unclea...Understanding susceptibility factors of sepsis is crucial for early diagnosis and development of personalized treatment strategies. However, the genetic determinants for initiation and progression of sepsis remain unclear. Here, we showed that the expression levels of estrogen receptor β (ERβ) were significantly reduced in the peripheral blood of patients with sepsis and were negatively correlated with disease severity. The results from human samples and experimental animals demonstrated that ERβ deficiency enhanced the body's susceptibility to sepsis by inducing macrophage pyroptosis, thereby impairing bacterial clearance. Mechanistically, ERβ deficiency enhanced fatty acid oxidation, increased acetyl-CoA levels, and promoted acetylation of stomatin-like protein 2 (Stoml2) at K221, leading to mitochondrial dysfunction and macrophage pyroptosis. Mutating the Stoml2 K221 site mitigated these effects and improved survival of septic mice. These findings suggest ERβ deficiency as a potential genetic factor in sepsis susceptibility.
Hua Z, Xu W, Ding W
… +12 more, Fu Z, Wang Y, Yang Y, Liu F, Dai Z, Tang W, Ou W, Ge W, Chen Y, Wang Z, Liu CY, Du P
J Clin Invest
· 2026 May · PMID 41842946
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The dynamic assembly and regulation of the IκB kinase (IKK) complex in the NF-κB pathway are central to the pathogenesis and progression of inflammatory bowel disease (IBD). We recently reported that the transcription fa...The dynamic assembly and regulation of the IκB kinase (IKK) complex in the NF-κB pathway are central to the pathogenesis and progression of inflammatory bowel disease (IBD). We recently reported that the transcription factor hematopoietically expressed homeobox (HHEX) promotes colitis-associated colorectal cancer, but the potential role of HHEX in intestinal inflammation remains uncharacterized. Here, we found that HHEX is upregulated in inflamed colons in a colitis mouse model and in clinical IBD samples. HHEX overexpression increased inflammatory cytokine expression, and HHEX loss largely abrogated the inflammatory response in vitro and intestinal inflammation in vivo. Mechanistically, IKKα phosphorylates HHEX at S213 to stabilize HHEX in response to TNF-α by inhibiting the interaction of HHEX with the E3 ubiquitin ligase MID2 and subsequent K48-linked ubiquitination and protein degradation. Importantly, HHEX interacted with and stabilized the IKKα/IKKβ complex via its N-terminal domain, thereby activating the NF-κB pathway and establishing a positive feedback loop that exacerbates intestinal inflammation. Our study reveals a transcription-independent function of HHEX in promoting IKK complex assembly and colitis, identifying HHEX as an IBD susceptibility gene and a potential target for IBD treatment.
Leone VA, Frazier K, Kaur M
… +9 more, Chrisler EA, Sidebottom AM, Tai E, Tran V, Li S, Chang EB, Jones DP, Van Cauter E, Hanlon EC
J Clin Invest
· 2026 Mar · PMID 41837293
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BACKGROUNDGut microbes and their metabolites contribute to the host circulating metabolome and exhibit diurnal variation influenced by sleep-wake cycles and meal timing. Sleep deprivation alters the rhythmic circulating...BACKGROUNDGut microbes and their metabolites contribute to the host circulating metabolome and exhibit diurnal variation influenced by sleep-wake cycles and meal timing. Sleep deprivation alters the rhythmic circulating metabolome, but its impact on microbial metabolites remains unclear. We tested whether 24-hour circulating metabolite profiles, including those of microbial origin, differ under normal (habitual) versus short-term restricted sleep.METHODSIn a randomized crossover design, 9 healthy adults completed 2 in-lab 24-hour blood sampling sessions (q120): one following 3 nights of normal sleep (8.5 hours/night), the other following 3 nights of sleep restriction (4.5 hours/night). Meal timing and caloric intake were held constant. Serum metabolites were characterized using untargeted reverse-phase liquid chromatography-mass spectrometry and rhythmicity was assessed using empirical JTK_CYCLE analysis.RESULTSWe identified 90 metabolites, including 14 of microbial origin or derived from host metabolism of microbial products, e.g., butyrate and tryptophan derivatives. Sleep restriction significantly altered serum metabolite composition compared with normal sleep. While many compounds maintained rhythmicity across conditions, sleep restriction disrupted rhythms of several key compounds, including microbe-derived metabolites. Notably, butyrate and indole-3-propionic acid lost rhythmicity, whereas new rhythms emerged in the tryptophan catabolite, kynurenine, and lipid metabolism intermediates.CONCLUSIONWe provide evidence that microbial metabolites are detectable in human blood and exhibit sleep-dependent rhythmicity. Sleep restriction alters diurnal circulating microbial and host-derived metabolite rhythms even under constant meal timing, composition, and calories. These findings support links between host sleep patterns and gut microbial metabolism and suggest microbial metabolites as potential biomarkers or mediators of sleep loss-associated health risks.TRIAL REGISTRATIONNCT00989976.FUNDINGNIH/NCRR KL2RR025000; R56DK102872-01A1, P30DK020595; P30DK042086; K01DK111785; F31DK122714; DOD W81XWH-07-2-0071.
Letizia M, Omar T, Weidner P
… +26 more, Jakob MO, Freise I, Krug SM, Löscher BS, Rosati E, Obermayer B, Gamez-Belmonte R, Hecker J, Ziegler JF, Weixler B, Asbach P, Kunkel D, Stumvoll M, Miehle K, Becker C, Klose CS, Glauben R, Beule D, Kühl AA, Conrad T, Tacke F, Wirtz S, Franke A, Sanders AD, Siegmund B, Weidinger C
J Clin Invest
· 2026 Mar · PMID 41837291
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Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in...Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn's disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell-intrinsic de novo neuroblastoma RAS viral oncogene homolog (NRAS) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD.
J Clin Invest
· 2026 Mar · PMID 41837290
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For over a decade, sepsis phenotyping has identified hyperinflammatory and hypoinflammatory subphenotypes using host biomarkers and clinical variables, without factoring in contributions from infectious insults across pa...For over a decade, sepsis phenotyping has identified hyperinflammatory and hypoinflammatory subphenotypes using host biomarkers and clinical variables, without factoring in contributions from infectious insults across patients. In this issue, Chanderraj and colleagues challenge this host-centric paradigm by demonstrating that pathogen characteristics independently contribute to sepsis subphenotypes. They reported that Enterobacterales infections, particularly Escherichia coli, strongly associated with hyperinflammatory subphenotypes, independent of illness severity. Bacterial burden, anatomic barrier breach, and circulating pathogen-associated molecular patterns influence phenotypic classification, with implications extending to culture-negative sepsis. Animal models supported causality, while reanalysis of an observational cohort and a clinical trial revealed that lactate clearance's prognostic value and therapeutic effects of endotoxin removal with polymyxin B hemoadsorption vary by subphenotype and pathogen. These findings lay groundwork for integrative host-pathogen phenotyping; for precision medicine in critical illness, we must know not only who is sick, but what made them sick, and how the two interact.
Buchtler S, Frühauf A, Neumayer S
… +13 more, Schmidbauer K, Talke Y, Winter-Köhler F, Balam S, Landgraf K, Gebhard C, Rehli M, Schlieckau FV, Beck M, Günther F, Fleck M, Renner K, Mack M
J Clin Invest
· 2026 Mar · PMID 41837289
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Repetitive injuries are an important trigger of progressive fibrosis. To study if repetitive injuries induce an accelerated profibrotic process, also called "fibrosis-memory," we established an experimental system with t...Repetitive injuries are an important trigger of progressive fibrosis. To study if repetitive injuries induce an accelerated profibrotic process, also called "fibrosis-memory," we established an experimental system with two consecutive, clearly separated insults in a model of renal fibrosis with reversible and irreversible unilateral ureteral obstruction. We found that a preceding fibrotic event of one kidney markedly enhanced subsequent development of fibrosis in the contralateral kidney. Aggravation of fibrosis during the second insult was dependent on memory CD4+ T cells. T cell depletion abrogated the fibrosis-memory effect, while adoptive transfer of memory T cells from fibrotic mice enhanced fibrosis in the recipients. Moreover, IL-3 production by memory CD4+ T cells was essential for aggravation of fibrosis in memory situations. In patients with systemic sclerosis, IL-3 expression by T cells was markedly increased, especially after a long disease duration accompanied by involvement of internal organs. In summary, our data identify IL-3-mediated fibrosis-memory as an important driver of progressive fibrosis.
J Clin Invest
· 2026 Mar · PMID 41837288
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The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpr...The TMPRSS2:ERG gene fusion is a truncal oncogenic event in a large subset of prostate cancers, yet its clinical relevance has remained unclear. In this issue of the JCI, Köcher et al. have demonstrated that ERG overexpression in human prostate cancer cells rewired DNA double-strand break repair toward a poly(ADP-ribose) polymerase 1-dependent (PARP1-dependent) alternative end-joining pathway without disrupting canonical repair. This repair bias created a conditional dependency on PARP1 that was exposed by radiotherapy, rendering ERG-positive tumors selectively sensitive to PARP inhibition-mediated radiosensitization. The tumor-selective cytotoxic effect of combined PARP1 inhibition and irradiation was corroborated in human-derived prostate cancer organoids. These findings establish ERG as a predictive biomarker for precision radiotherapy and highlight a tumor-selective strategy to enhance radiotherapeutic efficacy in prostate cancer.
Chanderraj R, Bartek B, Stringer KA
… +15 more, Tiba MH, Sjoding MW, He Y, Nuppnau M, Bongers KS, Adame MD, Lou SS, Kerschberger VE, Churpek MM, Calfee CS, Tripathi S, Foster DM, Kellum JA, Dickson RP, Sinha P
J Clin Invest
· 2026 Mar · PMID 41837287
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BACKGROUNDSepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes ("hyperinflammatory" and "hypoinflammatory") have been consistently identified within sepsis via latent class anal...BACKGROUNDSepsis encompasses considerable biological and clinical heterogeneity. Previously, 2 phenotypes ("hyperinflammatory" and "hypoinflammatory") have been consistently identified within sepsis via latent class analysis. These phenotypes differ in their biological features, clinical outcomes, and therapeutic responses to interventions. Prior studies of sepsis heterogeneity have focused primarily on the host response. Here, we investigate the potential influence of the causative pathogen on sepsis heterogeneity and pathobiology.METHODSWe performed a retrospective observational analysis of 8,280 critically ill patients with sepsis to identify associations between pathogen characteristics and the hyperinflammatory and hypoinflammatory patient phenotypes. We also performed controlled murine and swine modeling of sepsis and lung injury and a secondary analysis of 449 patients enrolled in the EUPHRATES randomized controlled trial.RESULTSPathogen characteristics (pathogen identity, burden, virulence, and anatomic site of infection) were strongly and independently associated with the previously reported phenotypes. In a cohort of critically ill patients with sepsis, infection with gram-negative pathogens, primarily Enterobacterales spp. (e.g., Escherichia coli, Klebsiella pneumoniae), was strongly associated with the hyperinflammatory phenotype. The hyperinflammatory phenotype was also independently associated with increased pathogen burden, virulence, and initial anatomic site of infection. In controlled murine and swine modeling, both the identity and burden of the pathogen provoked key biological features of the hyperinflammatory phenotype. Among patients with sepsis, the prognostic value of lactate clearance varied substantially by phenotype. In a secondary analysis of a randomized trial of polymyxin B hemoadsorption (which removes circulating endotoxin), hypoinflammatory patients experienced worse survival.CONCLUSIONSOur results demonstrate the central importance of pathogen features in the clinical and biological heterogeneity of sepsis. Future studies of sepsis pathobiology and heterogeneity should expand their scope beyond the host response, as understanding pathogen-host interactions will be crucial in the development of precision therapeutic strategies to improve patient outcomes.TRIAL REGISTRATIONEUPHRATES trial NCT01046669.FUNDING5P30AG024824, IK2CX002766, R01HL144599, K24HL159247, R01HL158626, R01HL173531, R35GM142992, R35GM145330, R35GM136312, K23HL166880, R35HL140026.
Pache L, Bui JK, Klouser LM
… +23 more, Fennessey CM, Noyola AC, Einhaus T, Zhu H, Stensland L, Leguizamo I, Koroma AA, Teriete P, Chang WLW, Hyrien O, Duggan NN, Heimann D, Pérez-Osorio AC, Bar KJ, Cosford ND, Keele BF, Hartigan-O'Connor DJ, Farzan M, Gardner MR, Jerome KR, Chanda SK, Kiem HP, Peterson CW
J Clin Invest
· 2026 Mar · PMID 41837286
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Despite the success of antiretroviral therapy in controlling HIV replication, latent viral reservoirs persist, presenting a major barrier to a cure. Current treatment approaches that aim to reactivate latent virus and el...Despite the success of antiretroviral therapy in controlling HIV replication, latent viral reservoirs persist, presenting a major barrier to a cure. Current treatment approaches that aim to reactivate latent virus and eliminate infected cells, termed "shock and kill," hold promise but have yet to demonstrate meaningful reservoir reduction in vivo. In this study, we explored combining ciapavir, a Smac mimetic latency-reversing agent, with adeno-associated virus-delivered (AAV-delivered) eCD4-Ig to treat antiretroviral therapy-suppressed, SHIV-infected rhesus macaques. We could demonstrate that a Smac mimetic can induce modest reactivation of the latent SHIV reservoir, as evidenced by transient increases in plasma viremia. However, while AAV-expressed eCD4-Ig conferred partial protection against intrarectal SHIV challenge in uninfected animals, neither eCD4-Ig nor ciapavir reduced the viral reservoir in SHIV-infected rhesus macaques, as determined by total SHIV DNA and a 5-target intact provirus detection assay. Animals treated with the combination showed no significant differences in viral rebound kinetics post-analytical treatment interruption compared with controls. Additionally, repeated ciapavir dosing resulted in adverse effects in some animals, suggesting potential toxicity with repeat administration. These findings highlight the challenges in reducing viral reservoirs using this shock-and-kill approach, particularly in SHIV-infected models, and suggest that further optimization of both latency-reversing agent and immune-mediated clearance strategies is required.
J Clin Invest
· 2026 Mar · PMID 41837285
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Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are...Neurodegenerative diseases are characterized by protein misfolding and the selective vulnerability of specific neuronal subtypes. This selective vulnerability presents a paradox; most neurodegenerative disease genes are expressed broadly throughout the brain, and some ubiquitously, but only certain types of neurons are lost while others are resistant. The molecular basis for selective neuronal vulnerability has remained a mystery, but recent genomics technological innovations are starting to provide mechanistic insights. Here, we review how single-cell genomics techniques - single-cell transcriptomics, single-cell epigenomics, and spatial transcriptomics - advance our molecular understanding of selective vulnerability and neurodegeneration across Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington disease. Together, these approaches reveal the cell types affected in disease, define disease-associated molecular states, nominate candidate determinants of vulnerability and degeneration, and situate degenerating neurons within their local tissue context. Continued development and application of these techniques, including single-cell perturbation screens, will expand descriptive atlases of relevant cell types in health and disease and identify causal mechanisms, revealing the molecular basis of vulnerability and degeneration and informing therapeutic development.