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J. Clin. Invest., Apr 28 2026, e196374 | https://doi.org/10.1172/JCI196374 Iron overload in steatotic hepatocytes drives systemic metabolic dysfunction via alterations in hepatokine production

Hye Jin Jo^1,14, Ayoung Kim^2,3,4,14, Hyunsoo Rho^5,6,14, Ae Kyung Park¹, Gil-Hwan Kim¹, Seo Jeong Jo¹, Hao Yuxin¹, You-Jung Hong¹, Ji Min Yeon¹, Hwang Chan Yu⁷, Mi-Young Song⁸, Jeongwoo Park², Yeon Hee Jeong⁹, Sung Eun Hong¹⁰, Hyo Jin Yeon¹⁰, Da Young Oh¹¹, Philipp E. Scherer¹¹, Cheol Soo Choi¹², Dong Hyeon Lee⁹, Sung Hwan Ki¹³, Keon Wook Kang², Murim Choi¹⁰, Byung-Hyun Park⁷, Eun Ju Bae¹, Sang Geon Kim^2,3, Won Kim^9,*, and Chang Yeob Han^1,*

¹School of Pharmacy and Institute of New Drug Development, Jeonbuk National University, Jeonju, Republic of Korea
²College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
³College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk UniversitySeoul, Goyang-si, Gyeonggi-do, Republic of Korea
⁴Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA
⁵College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea
⁶Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul, Republic of Korea
⁷Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea
⁸Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju, Republic of Korea
⁹Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Republic of Korea
¹⁰Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
¹¹Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
¹²Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Republic of Korea
¹³MRC-OSTRC, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Chosun University, Gwangju, Republic of Korea
¹⁴These co-first authors contributed equally to this work

^*Corresponding authors: Prof. Won Kim, MD. , Prof. Chang Yeob Han, Ph.D.

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 act as critical mediators driving systemic metabolic dysfunction in MASLD. Ferroportin (FPN, SLC40A1), the sole cellular iron exporter, exhibits markedly reduced expression in hepatocytes of both human patients and mouse models with MASLD, concomitant with hepatic iron accumulation. Functionally, hepatocyte-specific FPN deletion significantly exacerbates 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 enhances the production of two 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 reverse 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.

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