Hepatocyte hedgehog signaling controls ferroptosis to alleviate aging-related organ dysfunction

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Abstract

Aging drives systemic metabolic dysfunction (SMD) and increases the risk of chronic illnesses such as metabolic dysfunction–associated steatotic liver disease (MASLD) and chronic kidney disease (CKD). However, mechanisms that connect aging to multi-organ deterioration are poorly understood. In this study, we identify hepatocyte Hedgehog signaling as a central regulator of ferroptosis. Using mice with hepatocyte-specific deletion of Smoothened (Smo), a key Hedgehog pathway component, we show that loss of hepatocyte Hedgehog signaling induces ferroptotic stress, lipid peroxidation, and cellular senescence. These changes were sufficient to cause spontaneous MASLD and to trigger secondary kidney injury. Smo deletion also disrupted systemic iron balance, increased hepatocyte production of the angiotensinogen, and reduced liver perfusion. Similar responses (iron dysregulation, vascular dysfunction, and reduced Hedgehog signaling) were observed in patients with MASLD and advanced fibrosis. Inhibition of ferroptosis with ferrostatin-1 reversed hepatocyte senescence, restored hepatic blood flow, and improved both liver and kidney injury in Smo-deficient mice. Overall, these findings show that hepatocyte Hedgehog signaling preserves liver homeostasis by restraining ferroptotic stress and coordinating iron-dependent vasoactive pathways. The results reveal an unrecognized aging-related communication axis between liver and kidney and identify the Hedgehog–ferroptosis pathway as a promising therapeutic target for age-associated metabolic diseases.

Authors

Ji Hye Jun, Rajesh K. Dutta, Soon-Woo Cho, Rui Yao, Seh Hoon Oh, Zhi Li, Kuo Du, David S. Umbaugh, Nanchao Wang, Yirui Xu, Jingting Li, Lingyan Shi, Jen-Tsan Chi, Junjie Yao, Anna Mae Diehl