Sexual dimorphism in liver fibrotic metabolic dysfunction: Effects of testosterone and estrogen on CCl4-induced liver injury in ovariectomy and orchiectomy models.

Liver fibrosis is closely linked to metabolic dysfunction and hormonal regulation, with sex differences influencing disease progression. This study combined untargeted liver metabolomic profiling with ovariectomy and orchiectomy mouse models to investigate the roles of estrogen and testosterone in liver injury caused by carbon tetrachloride (CCl₄). Estrogen deficiency aggravated fibrotic injury and liver dysfunction in female mice, whereas testosterone deficiency exerted relatively modest effects in males. Estrogen supplementation significantly attenuated fibrosis in estrogen-deficient females, while testosterone supplementation produced limited and context-dependent responses. Metabolomic profiling revealed hormone-specific metabolic remodeling: estrogen predominantly influenced tryptophan, glycerophospholipid, and nicotinate metabolism, whereas testosterone was associated with alterations in purine, taurine/hypotaurine, and cysteine-methionine pathways. Notably, glycerophospholipid metabolism emerged as a shared but oppositely regulated pathway between estrogen and testosterone exposure. These findings support the established protective role of estrogen and highlight sex-dependent differences in hormone-associated metabolic remodeling during liver fibrosis.