J Clin Invest
· 2026 Apr · PMID 41983396
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Thyroid hormones provide crucial regulation of energy expenditure through their effects on thermogenesis, lipid metabolism, and mitochondrial function. Given their close relationship with overall metabolism, a deficit in...Thyroid hormones provide crucial regulation of energy expenditure through their effects on thermogenesis, lipid metabolism, and mitochondrial function. Given their close relationship with overall metabolism, a deficit in thyroid hormones fittingly leads to a positive energy balance and weight gain. The direction of this process may also operate in reverse, according to recent research from Rampy et al. in this issue of JCI. These investigators found that mice introduced to a high-fat, high-sugar diet developed marked short-term intracellular stress and functional impairment in the thyroid gland, leading to alterations in serum thyroid hormone levels prior to measurable weight gain. This finding opens the possibility that thyroid dysfunction originates from persistent damage to the thyroid gland caused by sustained overnutrition.
Liu XY, Wang G, Yu Y
… +6 more, Xiao H, Oh-Hashi K, Shi X, Zheng S, Gerszten R, Kahn CR
J Clin Invest
· 2026 Apr · PMID 41983395
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Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction-associated steatotic liver d...Glutathione (GSH) maintains a reduced cellular environment and is widely believed to mitigate disease-associated oxidative damage to proteins, thereby protecting against metabolic dysfunction-associated steatotic liver disease (MASLD). However, this widely accepted assumption remains largely untested because of challenges in physiologically manipulating hepatic GSH levels during disease development. Here, we have utilized liver-specific overexpression of cation transport regulator homolog 1 (Chac1), a recently identified intracellular GSH-degrading enzyme, to induce hepatic GSH depletion during MASLD progression. Contrary to canonical doctrine, GSH depletion unexpectedly protects against MASLD by substantially decreasing hepatic lipogenesis and fibrosis without triggering an oxidative stress response. Mechanistically, GSH depletion does not cause global protein oxidation but instead selectively oxidizes and destabilizes fatty acid synthase while decreasing lipogenic gene expression at the transcriptional level, collectively suppressing lipogenesis. Interestingly, Chac1 expression is decreased in livers of patients with MASLD, highlighting its potential therapeutic relevance. These findings revise the conventional view of GSH in protein redox and demonstrate that targeted redox manipulation through GSH depletion protects against MASLD.
J Clin Invest
· 2026 Apr · PMID 41983394
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Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous...Skeletal muscle has the impressive capacity to completely regenerate even after relatively severe injuries in young individuals, but this process is dysregulated in multiple cell types in the microenvironment in numerous diseases and aging. In this issue of the JCI, Cao et al., using an elegant set of genetic mouse models and pharmacological approaches, demonstrated that gasdermin E (GSDME) was required in myeloid cells after sterile muscle injury to normally regenerate muscle and that downstream IL-18 release prevented intramuscular ectopic fat deposition. GSDME expression was reduced in human muscles from aged individuals, and Gsdme was increased after muscle injury in young, but not old, mice. The ability of IL-18 to partially improve regeneration in aged GSDME-knockout mice demonstrates the potential clinical relevance of this finding in dysregulated muscle regeneration associated with aging.
J Clin Invest
· 2026 Apr · PMID 41983393
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Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addresse...Abdominal aortic aneurysms (AAAs) are an age-related cause of sudden cardiac death and cardiovascular disease (CVD) morbidity with limited nonsurgical treatment options. In this issue of the JCI, Yonekawa et al. addressed the pathobiologic mechanisms of clonal hematopoiesis (CH), the age-related acquisition of expanded somatic clones in blood cells, as a potential driver of AAA. CH prevalence was high in patients being treated for AAA, and faster AAA expansion occurred over a period of one year in CH carriers. In an angiotensin II-induced model of AAA, mice carrying ten-eleven translocation 2 (Tet2) mutations (Tet2-CH) displayed accelerated AAA development and macrophage reprograming to an osteoclast-like state. Inhibition of this differentiation, targeting RANK/RANKL with FDA-approved therapies like alendronate and denosumab, suppressed aneurysmal growth. These findings suggest that macrophage-to-osteoclast differentiation may underlie the risk and progression of AAA associated with age-related CH, a mechanism that is modifiable through existing therapeutics.
Zhao Y, Zhou Y, Pan L
… +10 more, Tian GG, Huang HY, Tang S, Lu M, Zhou Z, Zhang P, Chen L, Zhang L, Hu L, Ji H
J Clin Invest
· 2026 Apr · PMID 41983392
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Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer in...Complete response is rarely observed in lung cancer molecular targeted therapy, despite great clinical success. Here, we found that molecular therapy targeted toward EGFR mutant, KRAS mutant, or ALK fusion lung cancer induced cholesterol biosynthesis, which promoted cancer cells to enter dormancy and thus escape drug killing. Combined statin treatments effectively blocked cholesterol biosynthesis, prevented cancer cells from entering dormancy, and thus resulted in dramatic tumor regression. We further identified a subpopulation of cycling cancer cells that persisted during molecular targeted therapy and remained sensitive to aurora kinase inhibitors. Triple-targeting cholesterol biosynthesis, aurora kinase, and individual oncogenic drivers almost eradicated all the cancer cells. Therapy-induced cancer dormancy was mainly attributed to activation of unfolded protein response, specifically the PERK-eIF2α axis, which triggers cholesterol biosynthesis and AKT signaling. Collectively, this work uncovers an unexpected role of a therapy-induced prosurvival program in promoting cancer dormancy and provides a potentially effective strategy to prevent drug resistance.
J Clin Invest
· 2026 Apr · PMID 41983391
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Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived...Neurodegenerative diseases arise from interactions among pathogenic proteins, immune responses, and diverse environmental or age-related stressors that disrupt CNS homeostasis. CNS resident microglia detect self-derived danger signals through pattern recognition receptors, and their activation can promote clearance of aberrant proteins, including amyloid-β, tau, α-synuclein, and TAR DNA-binding protein 43. However, microglial activation may also drive maladaptive states that amplify neuroinflammation. Microglial transitions are further shaped by receptor-mediated signaling and antigen presentation pathways that integrate environmental cues with functional responses. Adaptive immune cells contribute additional layers of regulation, with CD8+ and CD4+ T cells exerting neuroprotective or neurotoxic effects depending on disease context, activation state, and antigen specificity. The identification of granzyme K-expressing CD8+ T cells in several neurodegenerative conditions highlights the growing recognition that distinct T cell subsets may have specialized roles in disease. Aging, repetitive head injury, and viral infection further alter microglial phenotypes, weaken barrier integrity, promote T cell recruitment, and prime the CNS for chronic inflammation. In this review, we synthesize current knowledge of innate and adaptive immune mechanisms in neurodegeneration, examine how external factors influence these responses, and consider how these insights may guide future therapeutic strategies.
Mix MR, Sievers CM, Hassert M
… +16 more, Kannan SK, Pewe LL, Huang SC, He R, Fain CE, Heidarian M, Hancox LS, Arumugam SA, Beltz TG, Jin F, Johnson AJ, Carter CS, Butler NS, Salem AK, Badovinac VP, Harty JT
J Clin Invest
· 2026 Apr · PMID 41983390
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Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in e...Primary and metastatic brain tumors exhibit resistance to immunotherapies that demonstrate efficacy in peripheral cancer settings. While many immunotherapies aim to enhance CD8+ T cell infiltration and functionality in established tumors, identification of neoantigens support emerging immunopreventative tactics against brain cancer. Functionally potent tissue-resident memory CD8+ T cells (TRM) can be generated in the brain following peripheral infection or vaccination. However, the ability of brain TRM to prevent intracranial malignancy remains unknown. Here, mice were seeded with tumor-specific or bystander brain TRM via peripheral infection prior to depletion of circulating memory T cells (TCIRCM) and subsequent brain tumor challenge. Tumor-specific brain TRM durably protected mice against intracranial malignancy even in the absence TCIRCM. These brain TRM persisted in tumor-surviving mice and protected against a second antigen-matched challenge. Importantly, a translationally-relevant mRNA-lipid nanoparticle (LNP) vaccine phenocopied peripheral infection-induced outcomes, generating functional brain TRM that controlled tumor growth. Altogether, this work points to the utility of brain TRM in cancer immunoprevention, supporting the development of antitumor mRNA-LNP vaccines to bolster brain immunity.
Rasmussen LW, Luthra D, Moncada-Giraldo D
… +10 more, Lewis C, Soto-Vazquez YM, Li Z, Hu B, Dobosh BS, Stacks DA, Koff JL, Gaggar A, Tirouvanziam R, Margaroli C
J Clin Invest
· 2026 Jun · PMID 41979898
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The epidermal growth factor receptor influences how airway neutrophils clear bacteria in cystic fibrosis, revealing a novel mechanism in neutrophil biology.The epidermal growth factor receptor influences how airway neutrophils clear bacteria in cystic fibrosis, revealing a novel mechanism in neutrophil biology.
Darsono WHW, Hwang Y, Valencia E
… +7 more, Gunawan LT, Hyeon SJ, Ryu H, Stein TD, Chang MY, Wulansari N, Lee SH
J Clin Invest
· 2026 Jun · PMID 41955024
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Loss-of-function mutations in DNAJC6, encoding the cochaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson's disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons,...Loss-of-function mutations in DNAJC6, encoding the cochaperone auxilin (HSP40 family), cause familial juvenile-onset Parkinson's disease (PD). Given the chaperone role of DNAJC6 in cellular homeostasis in adult neurons, we hypothesized that DNAJC6 dysfunction may not be limited to juvenile-onset disorders but could also be associated with adult-onset brain diseases. Here, we show that DNAJC6 expression is significantly downregulated in postmortem substantia nigra tissues and transcriptomic datasets from patients with late-onset sporadic PD. Consistently, human pluripotent stem cell-derived midbrain cultures exhibited reduced DNAJC6 expression under multiple PD-associated conditions. Mechanistically, DNAJC6 loss resulted from impaired transcription mediated by the midbrain-specific factors NURR1/FOXA2 and reduced protein stability regulated by LRRK2. Beyond neurons, DNAJC6 was robustly expressed in astrocytes and similarly downregulated in sporadic PD contexts. Astrocytic DNAJC6 deficiency impaired phagocytic, autolysosomal, and mitochondrial functions while promoting a proinflammatory phenotype, thereby exacerbating neurodegenerative pathology. Importantly, epigenetic restoration of DNAJC6 in neurons and astrocytes using a CRISPRa-AAV9 system in the substantia nigra of an α-synuclein-induced PD mouse model alleviated behavioral deficits and neuropathology. These findings provide evidence that DNAJC6 dysregulation is associated with pathogenic processes in sporadic PD and suggest that targeting neuronal and astrocytic DNAJC6 could represent a potential disease-modifying strategy.
Mach KE, Kornberg Z, Shkolyar E
… +11 more, Long J, Lee TJ, La V, Yoo I, Rodriguez G, Thong AE, Prado KB, Shah JB, Leppert JT, Skinner EC, Liao JC
J Clin Invest
· 2026 Jun · PMID 41955017
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BACKGROUNDCurrent diagnosis and surveillance of bladder cancer rely on cystoscopy, which is invasive and user dependent. The urine mRNA panel, uRNAp, measures expression of 3 genes for identification of bladder cancer. H...BACKGROUNDCurrent diagnosis and surveillance of bladder cancer rely on cystoscopy, which is invasive and user dependent. The urine mRNA panel, uRNAp, measures expression of 3 genes for identification of bladder cancer. Here we report validation of uRNAp for patients undergoing initial workup for suspected bladder cancer and surveillance for bladder cancer.METHODSUrine specimens were prospectively collected prior to cystoscopy at 2 health care systems from patients without (detection cohort) or with (surveillance cohort) a history of bladder cancer. RNA was isolated from urine sediment for RT-qPCR to determine roundabout guidance receptor 1, corticotropin releasing hormone, and insulin-like growth factor 2 expression and calculate the uRNAp bladder cancer probability score.RESULTSIn the detection cohort, 547 samples were collected from 529 patients. There were 123 new diagnoses of bladder cancer in the detection cohort, and uRNAp demonstrated 98% sensitivity and 51% specificity for identification of bladder cancer. In the surveillance cohort, 1,543 samples were collected from 447 patients with 286 recurrences. uRNAp demonstrated 94% overall sensitivity with 43% specificity and 99% sensitivity for high-grade recurrence. The receiver operating characteristic area under the curve was 0.92 in the detection and 0.81 in the surveillance cohort. uRNAp scores significantly increased with tumor size and grade.CONCLUSIONProspective validation of uRNAp demonstrated a strong potential clinical utility as a noninvasive adjunct to cystoscopy for management of bladder cancer. uRNAp may be a useful triage tool to defer or expedite cystoscopy for patients undergoing detection or surveillance of bladder cancer.FUNDINGDepartment of Veterans Affairs BLR&D Merit Review I01 BX004962 to JCL.
J Clin Invest
· 2026 Jun · PMID 41945394
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BACKGROUNDFunctional B cell responses for both prevention and control of hepatitis B virus (HBV) infection remain poorly understood, including in the context of HBV/HIV coinfection.METHODSHere, we employed high-dimension...BACKGROUNDFunctional B cell responses for both prevention and control of hepatitis B virus (HBV) infection remain poorly understood, including in the context of HBV/HIV coinfection.METHODSHere, we employed high-dimensional single-cell analysis to assess global and hepatitis B surface antigen-specific (HBsAg-specific) B cells in a longitudinal cohort of incident HBV from the Multicenter AIDS Cohort Study, with a subset of the cohort living with HIV-1.RESULTSWe observed that prior HIV infection has negative consequences for B cell function in early post-acute HBV infection, including increased frequencies of atypical memory B cells and regulatory B cells, expression of the activation marker CD86 on multiple B cell subsets in chronic HBV (CHB), and restricted expansion of HBsAg-specific B cells. In contrast, in HBV monoinfection, we observed no changes in the global B cell population from prior to infection and robust expansion of HBsAg-specific B cells. These expanded antigen-specific B cells resembled class-switched intermediate and resting memory B cells, with activation phenotypes that may contribute to ongoing HBV control.CONCLUSIONHIV infection has a significant impact on B cell responses to subsequent HBV infection that may promote development of CHB in HBV/HIV coinfection.FUNDINGVaccine Research Center, NIAID, Bill & Melinda Gates Foundation, and NIH.
Fang B, Li X, Lu Y
… +13 more, Ma W, Gan H, Zhang T, Liu Q, Wang B, Wang Z, Zhu Y, Zhu H, Xiao S, Bian X, Wei G, Ye D, Zhu Y
J Clin Invest
· 2026 Jun · PMID 41945392
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Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody-drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinic...Metastatic castration-resistant prostate cancer (mCRPC) remains lethal with limited treatment options. Antibody-drug conjugates (ADCs) have emerged as a transformative class across multiple solid tumors, yet their clinical application in prostate cancer has been limited. Izalontamab brengitecan (Iza-bren; BL-B01D1) is a bispecific ADC-targeting EGFR and HER3 that has demonstrated activity in other malignancies. Here, we evaluated its therapeutic potential in the treatment of prostate cancer. Multi-omics analyses revealed frequent EGFR and HER3 expression in CRPC adenocarcinoma but not in neuroendocrine subtypes. BL-B01D1 exerted potent, target-dependent cytotoxicity in prostate cancer cell lines, xenografts, and patient-derived organoids (PDOs). We highlight a representative patient with mCRPC with high EGFR/HER3 expression whose disease rapidly and durably mounted a clinical and radiologic response to BL-B01D1, concordant with matched PDO sensitivity. Mechanistic studies identified ABCG2 upregulation as a driver of acquired resistance, with genetic or pharmacologic inhibition restoring BL-B01D1 sensitivity. Importantly, tumor tissue obtained at progression after BL-B01D1 treatment confirmed ABCG2 upregulation, validating a clinically relevant resistance mechanism. These findings support BL-B01D1 as a promising therapeutic strategy in mCRPC and indicate ABCG2 may be a rational target for overcoming resistance.
Joo NS, Birket SE, Keith JD
… +10 more, Ianowski JP, Luan X, Spano J, Bollyky JB, Dobry MN, Sabater JR, Williams RW, Engelhardt JF, Wine JJ, Milla CE
J Clin Invest
· 2026 Jun · PMID 41926225
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Mucociliary clearance (MCC) is an innate defense mechanism that normally keeps airways clean but is dysfunctional in cystic fibrosis (CF) and other muco-obstructive pulmonary diseases. Previously we discovered that activ...Mucociliary clearance (MCC) is an innate defense mechanism that normally keeps airways clean but is dysfunctional in cystic fibrosis (CF) and other muco-obstructive pulmonary diseases. Previously we discovered that activating adenyl cyclase in combination with a cholinergic agonist increased MCC velocity (MCCV) synergistically in ex vivo WT and CF ferret and WT piglets. For what we believe is the first time, we show in vivo synergistic MCC using FDA approved β-adrenergic and cholinergic drugs delivered to the apical surface of WT and CF rats and a CF sheep model. Also, a single dose of the combined drugs is tolerated by humans. As for mechanisms, via ex vivo experiments, we show the combined agonists increased net fluid secretion mainly by stimulating gland secretion and by inhibiting surface absorption, consequently increasing airway surface liquid depth. They also increased net base secretion and increased ciliary beat frequency. Additional ex vivo and in vitro experiments show that the combined agonists had additive effects when combined with highly effective CF transmembrane conductance regulator modulator therapy. The synergistic increase in MCCV induced by this combination of agonists offers therapeutic potential for treating muco-obstructive pulmonary diseases, including CF.
Massanella M, Dufour C, Pagliuzza A
… +21 more, Lemieux A, Richard C, Ananworanich J, Leyre L, Jupimai T, Buranapraditkun S, Nantanee R, Mitchell JL, Sawangsinth P, de Souza M, Suntarattiwong P, Kanjanavanit S, Kosalaraksa P, Borkird T, Petdachai W, Chokephaibulkit K, Trautmann L, Fromentin R, Puthanakit T, Chomont N, HIV Netherlands Australia Thailand Research Collaboration 209 and 194 (HIVNAT209 and HIVNAT194) study groups
J Clin Invest
· 2026 Jun · PMID 41926220
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Early initiation of antiretroviral therapy (ART) in perinatally HIV-infected children significantly limits the establishment of the viral reservoir. However, the long-term impact of this intervention remains unclear. We...Early initiation of antiretroviral therapy (ART) in perinatally HIV-infected children significantly limits the establishment of the viral reservoir. However, the long-term impact of this intervention remains unclear. We measured the frequency of inducible, translation-competent, and replication-competent proviruses in samples from 62 children who initiated ART early and remained virally suppressed for up to 9.9 years. Only a small fraction of HIV genomes produced HIV transcripts, viral proteins, or infectious virions. Accordingly, replication-competent virus was detected in only 11% of the participants. Despite the predominance of naive cells in pediatric blood, most proviruses were detected in memory CD4+ T cells, especially central memory cells. Longitudinal analysis revealed a biphasic decay in HIV DNA: an initial decline followed by long-term stability, which was associated with extensive expansions of infected T cell clones. In contrast, inducible proviruses declined continuously and became undetectable in most children after 5 years. Near full-length sequencing of 1,305 HIV genomes revealed a dramatic reduction in genetically intact proviruses, from pre-ART to after 7 years of ART. Together, these findings suggest that the intact viral reservoir rapidly decays in early-treated children, offering critical insights for pediatric HIV cure strategies.
Wang JL, Wang JC, Pan Y
… +17 more, He M, Zheng Z, Zou H, Wu T, Zhang Y, Hu Z, Fu Y, Peng W, Yang Z, Xu L, Zhang YJ, Chen MS, Hu D, Chen J, Zhao M, Chen DP, Zhou ZG
J Clin Invest
· 2026 Jun · PMID 41926218
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Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkp...Immunotherapies achieve durable responses in several cancers but show limited efficacy in refractory hepatocellular carcinoma (HCC). The mechanisms by which hepatoma cells evade immune recognition and limit immune checkpoint blockade (ICB) efficacy are incompletely defined. Here, we identified tumor-intrinsic tescalcin (TESC) as a previously unrecognized phagocytic checkpoint that contributes to immune evasion and ICB resistance in HCC. Mechanistically, H3K4 methylation drove TESC expression in hepatoma cells, facilitating cytosolic Ca2+ buffering and attenuating endoplasmic reticulum (ER) stress-induced calreticulin (CALR) plasma membrane exposure, an essential "eat-me" signal. Consequently, this process abrogated membrane CALR-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and DCs, thereby impairing antigen presentation and subsequent T cell activation. Clinically, we found that elevated H3K4me3-TESC signaling was a promising prognostic biomarker for a poor ICB response in HCC. Importantly, in vivo disruption of this axis restored APC phagocytic function and enhanced the antitumor effects of ICB therapy. Therefore, targeting TESC-driven immune escape and its underlying epigenetic regulation may restore APC function and offer a precise therapeutic strategy to enhance immunotherapeutic efficacy in HCC.
Lu Z, Shuai Y, Wang C
… +12 more, Liu Z, Wang Z, Liu Q, Jiang R, Zhu J, Zhu Y, Liao W, Zhu X, Zhao J, Shi K, Shi W, Gong P
J Clin Invest
· 2026 Jun · PMID 41926211
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Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor proinflammatory NLRP3+ microglia, in stark...Traumatic brain injury (TBI) disproportionately affects the elderly, yet the underlying mechanisms remain unclear. Here, we demonstrate that aged TBI brains predominantly harbor proinflammatory NLRP3+ microglia, in stark contrast to the neuroprotective Lysozyme+ microglia prevalent in young TBI brains. This age-dependent microglial dichotomy correlates with elevated mortality and impaired recovery in aged TBI mice. By leveraging an integrative multiomics approach combined with metabolomics and epigenome analysis, we identified a previously unrecognized link between enhanced glycolysis and the proinflammatory chromatin landscape in NLRP3+ microglia. Further investigation identified ELF1 as a key transcription factor driving NLRP3+ microglia formation. Importantly, ablation of ELF1 reversed age-associated microglial dysfunction and improved TBI outcomes. Finally, we report that Imeglimin, a clinically approved antihyperglycemic agent capable of crossing the blood-brain barrier, inhibits ELF1 and reverses microglial phenotype, reducing acute mortality rate and leading to improved functional recovery of aged mice with TBI. Our work elucidates the mechanistic basis of age-dependent TBI outcomes, reveals the crosstalk between metabolic rewiring and epigenetic regulation in microglial aging, and identifies ELF1 as a promising therapeutic target for improving TBI outcomes.
Koo YD, Castillo RT, Sukumaran Nair A
… +26 more, Garneau M, Gochee C, Campbell ZV, Vakil TS, Ha J, Marti A, Soto J, Das D, Martinez-Lopez N, Sharma S, Delgado Y, Phung C, Ashley IA, Kapelczak ED, Jacobo R, Weatherford ET, Dai DF, Benhammou JN, Marshall AG, Hinton A, Yang L, Pereira RO, TeSlaa T, Bouhaddou M, Singh R, Abel ED
J Clin Invest
· 2026 Jun · PMID 41926189
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Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute t...Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are leading causes of cirrhosis and hepatocellular carcinoma. Defects in autophagy contribute to the development of MASLD; however, the role of Unc-51-like autophagy-activating kinase 1 (ULK1) in the pathophysiology of MASLD remains unclear. Herein, we show that ULK1, a serine/threonine kinase and core autophagy protein, is significantly repressed in human MASH livers, and that hepatocyte-specific loss of ULK1 promotes, unexpectedly, hepatic steatosis and progression to liver fibrosis, without affecting basal autophagy flux. Phospho-proteomics identified the transcriptional coactivator NCOA3 as a downstream phospho-target of ULK1. Mechanistically, ULK1 phosphorylates NCOA3 to repress its transcriptional activity and restrain the CREB/CBP-mediated de novo lipogenic program. Accordingly, a phosphorylation-deficient NCOA3 mutant drives CREB/CBP-mediated lipogenesis, whereas genetic or pharmacological NCOA3 inhibition prevents steatosis, hepatic inflammation, and profibrotic signaling. Hence, ULK1-mediated NCOA3 phosphorylation is a fundamental and druggable checkpoint against the entire MASLD spectrum.
Kawai M, Fukuda A, Ikeda M
… +22 more, Iimori K, Mizukoshi K, Iwane K, Yamakawa G, Omatsu M, Namikawa M, Sono M, Masuda T, Fukunaga Y, Nagao M, Araki O, Yoshikawa T, Ogawa S, Hiramatsu Y, Tsuda M, Maruno T, Nakanishi Y, Saur D, Tsuruyama T, Masui T, Hatano E, Seno H
J Clin Invest
· 2026 Apr · PMID 41919507
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Katkeviciute E, Hering L, Montalban-Arques A
… +19 more, Busenhart P, Schwarzfischer M, Manzini R, Conde J, Atrott K, Lang S, Rogler G, Naschberger E, Schellerer VS, Stürzl M, Rickenbacher A, Turina M, Weber A, Leibl S, Leventhal GE, Levesque M, Boyman O, Scharl M, Spalinger MR
J Clin Invest
· 2026 Apr · PMID 41919506
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