Syringic acid suppresses ferroptosis of skeletal muscle cells to alleviate lower limb ischemia/reperfusion injury in mice via the HMGB1 pathway

Abstract Ischemia/reperfusion (I/R) of skeletal muscle in the lower limbs is an important factor affecting the outcome of lower limbs ischemia patients, with no effective preventive or therapeutic approaches available. The study was to investigate the effect of syringic acid (SA) on I/R skeletal muscle in the lower limbs injury. Mice femoral artery I/R models and C2C12 cell hypoxia/reoxygenation (H/R) models was establish, tissue damage, inflammatory status, and high mobility group box 1 (HMGB1) pathway were evaluated using histological analysis, enzyme‐linked immunosorbent assay, and western blotting. Further, the study detected the effect of SA on cell apoptosis, lipid peroxidation, Fe 2+ level, and ferroptosis‐related proteins expression. Finally, the effect of HMGB1 expression on SA in H/R stimulation was studied. SA alleviated pathological damage and reduced levels of IL‐1β, IL‐6, and TNF‐α in muscle tissues from femoral artery I/R mouse models. SA upregulated Bcl‐2 and SOD as well as downregulated Bax, MDA, TBARS content, and Fe 2+ level in H/R‐induced cells. SA inhibited HMGB1 expression and promoted Nrf2, HO‐1, GPX4, and SLC7A11 expressions in the injured tissues and cells. Such effects of SA on H/R‐induced cells were rescued by HMGB1 overexpression. SA suppressed ferroptosis of skeletal muscle cells to alleviate lower limb I/R injury in mice by blocking the HMGB1 pathway, providing new insights for the treatment of lower limb ischemia–reperfusion injury.