Abstract Background There is a gap in understanding the predominance of males with idiopathic pulmonary fibrosis (IPF). While gonadal hormones contribute to fibrosis susceptibility, evidence suggests a role for sex chromosomes. Methods We used The Four Core Genotypes (FCG) mouse model, which uncouples gonadal sex from sex chromosomes, in aged mice before and after bleomycin (BLM)-induced lung injury. Fibrosis severity was assessed by histology, collagen content, and profibrotic gene expression, along with analysis of estrogen receptor (ER)α and ERβ signaling, matrix metalloproteinase activity, insulin-like growth factor-1 (IGF-1), and microRNAs. Data were analyzed using two-way ANOVA to test effects of gonadal sex, sex chromosome complement, and their interaction; gonadectomy experiments used three-way ANOVA including gonadal status. Results BLM-induced lung injury resulted in the greatest fibrosis in XY mice with ovaries, which was associated with elevated ERα expression and increased ERα:ERβ ratio. In contrast, ERβ expression was highest in XX mice with testes and associated with attenuated fibrosis. Multiple fibrotic pathways were regulated by gonadal sex, sex chromosome complement, or their interaction. Gonadectomy revealed organizational and activational effects of sex hormones and uncovers interactions between gonadal sex, sex chromosomes, and hormone status. Sex chromosome–dependent regulation of let-7d and miR-29a linked chromosomal dosage to ERα–IGF-1 mediated remodeling. Conclusions These findings identify hormonal and chromosomal mechanisms contributing to sex bias in pulmonary fibrosis and suggest sex-informed therapeutic targets for IPF.
Elliot et al. (2026) studied this question.