Research Article
Abstract
Iron overload has emerged as a significant risk factor for metabolic dysfunction–associated steatotic liver disease (MASLD), a growing global health concern. Despite this association, the precise mechanisms by which hepatic iron and its regulatory genes connect liver pathology to systemic metabolic dysfunction remain elusive. Here, we demonstrate that humoral signals originating from iron-overloaded hepatocytes acted as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibited markedly reduced expression in hepatocytes of both patients with MASLD and mouse models of the disease, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbated diet-induced obesity and insulin resistance, with these metabolic perturbations accompanied by decreased energy expenditure and impaired thermogenic capacity. Mechanistically, we establish that hepatic iron accumulation resulting from FPN deficiency enhanced the production of 2 specific hepatokines, fetuin-A and LECT2, through activation of the transcription factor FoxO1. Notably, therapeutic interventions — including genetic silencing of these hepatokines, hepatocyte-specific FPN overexpression, or oral iron chelation — effectively reversed the metabolic dysfunction phenotypes. These findings provide critical insights into the pathophysiological mechanisms linking MASLD to systemic metabolic disorders and highlight promising therapeutic strategies to combat these diseases.
Authors
Hye Jin Jo, Ayoung Kim, Hyunsoo Rho, Ae Kyung Park, Gil-Hwan Kim, Seo Jeong Jo, Hao Yuxin, You-Jung Hong, Ji Min Yeon, Hwang Chan Yu, Mi-Young Song, Jeongwoo Park, Yeon Hee Jeong, Sung Eun Hong, Hyo Jin Yeon, Da Young Oh, Philipp E. Scherer, Cheol Soo Choi, Dong Hyeon Lee, Sung Hwan Ki, Keon Wook Kang, Murim Choi, Byung-Hyun Park, Eun Ju Bae, Sang Geon Kim, Won Kim, Chang Yeob Han
Abstract
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.
Authors
Zhichao Lu, Yi Shuai, Chenxing Wang, Zongheng Liu, Ziheng Wang, Qianqian Liu, Rui Jiang, Jue Zhu, Yongqi Zhu, Weiquan Liao, Xingjia Zhu, Jingwei Zhao, Kaibin Shi, Wei Shi, Peipei Gong
Abstract
Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1–dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.
Authors
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
Abstract
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids’ levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2–/– mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid–stimulated α cell proliferation and islet hormone secretion.
Authors
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
Abstract
Stroke remains a leading cause of morbidity and mortality worldwide, with few effective interventions to promote recovery. Targeting circadian timing and glymphatic function may represent viable therapeutic strategies. Here, we show that the small-molecule clock modulator, KL001; high-dose melatonin; acute light pulses; and active-phase time-restricted feeding were each sufficient to enhance glymphatic function in mice. Moreover, initiating treatment with either KL001 or active-phase time-restricted feeding 3 days after preclinical models of stroke improved motor outcomes, reduced lesion volume, increased glymphatic flow, and lowered poststroke brain cytokine burden. These findings suggest that reinforcing normal daily rhythmicity after stroke can markedly enhance neurological recovery, even when interventions are initiated several days after stroke onset.
Authors
Emma Waight, Yuxi Zhu, Ashley Caudell, Velia S. Vizcarra, Evan Newbold, Michael J. Giannetto, Evalien Duyvestyn, Estephanie Balbuena, Wei Song, Tanzil M. Arefin, Yuki Mori, Maiken Nedergaard, Lauren M. Hablitz
Abstract
Vitiligo is an autoimmune skin disease characterized by depigmentation, mainly due to CD8+ T cell–mediated destruction of melanocytes. Hyperglycemia exacerbates autoimmune responses and is associated with vitiligo; however, the underlying immunometabolic mechanisms are poorly understood. Here, we demonstrated the correlation between hyperglycemia and vitiligo in a case-control study and demonstrated that hyperglycemia aggravated vitiligo based on a mouse model. Targeted metabolomics identified succinate as the potential metabolite mediating hyperglycemia-aggravated vitiligo. Mechanistically, succinate promotes the activation of CD8+ T cells through succinate receptor 1 (SUCNR1) and promotes keratinocytes to secrete CXCL9 and CXCL10 by enhancing the stability and nuclear translocation of hypoxia-inducible factor-1α, facilitating the skin-homing of CD8+ T cells. Thus, hyperglycemia aggravates vitiligo through succinate/SUCNR1 axis–regulated CD8+ T cell hyperactivation. Our study provides insights into the long-observed yet previously unclear mechanism by which hyperglycemia accelerates vitiligo progression and highlights SUCNR1 as a potential therapeutic target.
Authors
Pan Kang, Yuqian Chang, Tingting Wang, Xiuli Yi, Yinghan Wang, Pengran Du, Jiaxi Chen, Baizhang Li, Shuli Li, Zhongjun Shao, Jianru Chen, Chunying Li
Abstract
The blood and lymphatic vascular systems are regulated by angiopoietin (ANGPT) growth factors, which signal via endothelial TIE receptor tyrosine kinases and integrins. However, mechanistic understanding of how these receptors crosstalk is limited. Here, we show how β1-integrin inactivation regulates endothelial ANGPT/TIE2 signaling. By integrating biophysical analyses, X-ray crystallography, size-exclusion chromatography–small-angle X-ray scattering and atomistic molecular dynamics simulations, we show that ANGPT2 binds through its asymmetrically positioned C-terminal fibrinogen-like domains to both TIE2 and α5β1-integrin, forming a trimeric complex compatible with the inactive α5β1-integrin conformation. Inactive β1-integrin colocalizes with ANGPT-induced TIE2 in cell-cell junctions and stabilizing β1-integrin in its inactive state enhances junctional TIE2 accumulation and promotes nuclear exclusion of the TIE2 transcriptional effector FOXO1 in cultured endothelial cells. Endothelial-specific β1-integrin deletion in adult mice reduces venous TIE2 phosphorylation, whereas endotoxemia diminishes junctional β1-integrin along with decreased phosphorylated TIE2. In contrast, without TIE2, ANGPT2 uniquely engages active β1-integrin, via its N-terminal superclustering domain. Altogether, our results provide structural and mechanistic evidence of ANGPT signaling via α5β1-integrin and support a model in which inactive α5β1-integrin acts as a junctional scaffold for ANGPT/TIE2/FOXO1 signaling, explaining how integrin conformational switching spatially organizes growth factor signaling in the endothelium.
Authors
Tuomas Sipilä, Srinivas Kumar Ponna, Abhinandan Venkatesha Murthy, Anne Pink, Giray Enkavi, Shraman Kumar Bohra, Klaudia Lewna, Keerthana Ganesh, Qina Liu, Mirka Korhonen, Tommi Kajander, Michael Potente, Johanna Ivaska, Ilpo Vattulainen, Veli-Matti Leppänen, Pipsa Saharinen
Abstract
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.
Authors
Wahyu Handoko Wibowo Darsono, Yeongran Hwang, Erica Valencia, Leonardo Tejo Gunawan, Seung Jae Hyeon, Hoon Ryu, Thor D. Stein, Mi-Yoon Chang, Noviana Wulansari, Sang-Hun Lee
Abstract
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.
Authors
Bangwei Fang, Xiaomeng Li, Ying Lu, Weiwei Ma, Hualei Gan, Tingwei Zhang, Qi Liu, Beihe Wang, Zixian Wang, Yi Zhu, Hai Zhu, Sa Xiao, Xiaojie Bian, Gonghong Wei, Dingwei Ye, Yao Zhu
Abstract
CoA facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3′ position of the ribose ring to form dephospho-CoA. Recent studies have shown that CoA, similar to glutathione, is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining a functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a link between CoA degradation, mitochondrial integrity, and muscle health.
Authors
Chao-Chieh Lin, Joshua Rose, Alexander A. Mestre, Chien-Kung Cornelia Ding, Ssu-Yu Chen, Sze Mun Choy, Kah Yong Goh, Weiyi Jiang, Wen Xing Lee, Qizhou Jiang, Yanting Chen, Tianai Sun, Jianli Wu, Yueqi Chen, Yunju Oh, Pyeonghwa Jeong, Jiyong Hong, Kenon Chua, Michael C. Fitzgerald, Guo-Fang Zhang, Hong-Wen Tang, Pei Zhou, Jen-Tsan Chi
No posts were found with this tag.
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)