Effects of moderate- and high-intensity aerobic exercise on hepatic iron homeostasis, ferroptosis-related changes, and lipid metabolism in high-fat diet-induced MASLD rats.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with disrupted iron homeostasis, lipid peroxidation, and ferroptosis-related liver injury. Although exercise is recommended for MASLD management, whether moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) exert comparable effects on hepatic iron metabolism and ferroptosis-related changes remains unclear. This study compared the effects of MICT and HIIT on hepatic iron homeostasis, ferroptosis-related markers, and lipid metabolic remodeling in high-fat diet (HFD)-induced MASLD rats. Forty male Sprague-Dawley rats were assigned to a normal-fat diet group or an HFD group. After 8 weeks of HFD feeding, HFD-fed rats were further divided into HFD control, MICT, and HIIT groups and underwent an additional 8-week intervention. HFD feeding induced metabolic dysfunction, hepatic steatosis, liver injury, iron accumulation, increased activation-related markers of the IL-6/JAK2/STAT3-hepcidin pathway, and ferroptosis-related changes, including reduced GPX4 and increased PTGS2 and MDA. Both MICT and HIIT improved metabolic and histological outcomes, reduced hepatic Fe2+ accumulation and lipid peroxidation, increased FPN1 expression, decreased DMT1 expression, reduced activation-related markers of IL-6/JAK2/STAT3-hepcidin signaling, and improved antioxidant defense. Untargeted lipidomics indicated partial remodeling of HFD-induced disturbances in glycerophospholipid, glycerolipid, sphingolipid, ether lipid, thermogenesis, insulin-resistance, and AMPK-related pathways. Most endpoint outcomes did not differ significantly between MICT and HIIT. Because no pathway-specific manipulation, iron-rescue experiment, or ferroptosis inhibitor was used, the present data do not establish that the IL-6/JAK2/STAT3-hepcidin-FPN1 axis causally mediates the exercise response. Instead, the findings indicate that MICT and HIIT exert broadly comparable protective effects that are associated with improved hepatic iron homeostasis, lower ferroptosis-related susceptibility, and hepatic lipid metabolic remodeling.