• SS-USCs exhibit superior tissue repair and antioxidant capabilities compared to RS-USCs, as revealed by multi-omics analyses.
• SS-USCs-derived exosomes (SS-USCs-Exo) significantly inhibit ferroptosis and alleviate severe fatty liver ischemia-reperfusion injury in vivo and in vitro.
• The therapeutic mechanism involves the delivery of GPX4 protein via exosomes, which suppresses ferroptosis and enhances cellular viability.
• SS-USCs are identified as the most suitable cell subtype for treating severe fatty liver IRI, offering a promising strategy to expand the donor liver pool.