Abstract Rationale Idiopathic pulmonary fibrosis (IPF) exhibits a strong male predominance, yet the mechanisms driving this disparity remain poorly understood. Although gonadal hormones modulate profibrotic signaling, growing evidence indicates that sex-biased expression of X- and Y-linked genes also contributes to the regulation of fibrotic pathways. Because fibrosis reflects an integrated response to both gonadal hormone and sex-chromosome signals, we hypothesized that interactions between sex-chromosome complement and gonadal hormones regulate key profibrotic mechanisms in the lung. Methods The Four Core Genotypes (FCG) mouse model was used to separate chromosomal sex (XX vs. XY) from gonadal sex (ovaries vs. testes) in aged mice subjected to bleomycin (BLM)-induced lung fibrosis. Fibrosis severity was assessed by weight loss, collagen content, and expression of insulin-like growth factor (IGF)-1, estrogen receptor (ER)α and ERβ, matrix metalloproteinases (MMPs), and matrix-regulating microRNAs (let-7d and miR-29a). Gonadectomy (GDX) was performed to distinguish activational effects of circulating gonadal hormones from organizational effects established earlier in life. Results Fibrosis severity varied by both sex-chromosome complement and gonadal hormone status in intact mice. XY mice with ovaries (XYF) developed the most severe fibrosis, suggesting synergistic effects of Y-linked profibrotic genes and the ovarian hormonal environment. GDX partially modulated ER subtype expression, MMPs and antifibrotic miRNA expression in all groups, indicating hormonal regulation, whereas chromosomal effects persisted post-GDX, demonstrating independent genetic contributions. Our data show that changes in sex hormone levels coupled with Y-linked gene activity converge on TGF-β, IGF-1, and ERα signaling pathways to promote fibrosis. Conclusions Sex differences in pulmonary fibrosis result from the interplay between sex-chromosome complement and gonadal hormones rather than either factor alone. Circulating hormone levels alone cannot explain disease susceptibility, as local receptor activity, miRNA regulation, and chromosomal context modify hormonal effects. These findings underscore the need for integrated approaches that incorporate hormonal, receptor-level, and genetic sex determinants to better understand and address sex-based disparities in IPF. This abstract is funded by: NIA
Grimaldo et al. (Fri,) studied this question.