Phloretin inhibits ferroptosis by restoring the antioxidant capacity of bovine adipose and muscle cells via the AMPK-PPAR signaling pathway

作者：Jie Li, Enhui Jiang, Mengyang Zhang, Chuanying Pan, Chuzhao Lei, Lin Han, Xianyong Lan · 发表于：Stress Biology · 年份：2025 · DOI：10.1007/s44154-025-00263-4 · 被引用次数：6 · 研究领域：Ferroptosis and cancer prognosis、Immune cells in cancer、Cancer-related molecular mechanisms research

Abstract Ferroptosis has been increasingly implicated in adipose and muscle dysfunction, systemic metabolic disturbances, and several diseases in livestock, which necessitates effective and side-effect-free inhibition strategies. Phloretin, a dihydrochalcone with excellent antioxidant and anti-inflammatory properties, may have the potential to restrain cell ferroptosis. Herein, phloretin was verified to significantly inhibit (1S,3R)-RSL3-induced ferroptosis by reducing intracellular MDA, Fe 2 ⁺, and ROS levels and restoring cell total antioxidant capacity in bovine and mouse preadipocytes or myoblasts. It also alleviated oxidative stress (OS), a vital inducer of ferroptosis, by restoring antioxidant enzyme activity in the above cells and obese mice. In vivo, phloretin gavage significantly reversed the trend where high-fat diet (HFD)-induced OS promoted the expression of ferroptosis-promoting genes and proteins (e.g., ACSL4 and PTGS2) while inhibiting the expression of ferroptosis-negative regulators (e.g., Fth1 and Gpx4 ). Unlike most flavonoids that exert anti-inflammatory or antioxidant activities by altering the gut microbiota composition, metagenomic sequencing analysis of cecal contents from phloretin-gavaged and HFD mice revealed that phloretin exerts its antioxidative and ferroptosis-inhibitory effects independent of modulating gut microbiota diversity. Further transcriptomic analyses of mouse adipose tissues revealed that phloretin alleviated ferroptosis in adipocytes...