Abstract

Heat stress (HS) induced by high ambient temperatures markedly disrupts metabolic homeostasis and meat quality development in ruminants, with reduced intramuscular fat (IMF) deposition is considered a major contributor to meat quality deterioration. However, the roles and underlying mechanisms by which inflammatory responses and ferroptosis in the regulation of IMF deposition in Hu sheep under HS conditions remain unclear. This study showed that HS markedly increased the production of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-8, and induced activation of the NF-κB signaling cascade, thereby suppressing the expression of the anti-ferroptotic enzyme glutathione peroxidase 4 (GPX4). These changes resulted in excessive accumulation of reactive oxygen species, enhanced lipid peroxidation, elevated ferrous iron (Fe 2+ ) levels, ultimately inducing ferroptosis. Further analyses demonstrated that blocking inflammatory responses or inhibiting NF-κB signaling restored GPX4 expression and alleviated ferroptosis, thereby improving fat deposition under HS conditions. Collectively, these findings demonstrate that HS modulates ferroptosis through the “inflammatory cytokine–NF-κB/GPX4 signaling axis,” thereby modulating IMF accumulation in Hu sheep. This study provides new mechanistic insights and potential intervention targets for improving meat quality in sheep under high-temperature conditions.