Palmitic acid exposure disrupts blood-testis barrier integrity via CHFR-mediated ubiquitination and degradation of SMARCD1 in male mice.

Palmitic acid (PA), a saturated fatty acid abundant in the diet and environment, has been closely associated with male reproductive dysfunction. However, the molecular basis of PA on the blood-testis barrier (BTB) disruption remains unclear. In this study, the chromatin remodeling factor SMARCD1 is identified as a key mediator of PA-induced testicular injury. PA exposure reduced the viability of Sertoli cells and Leydig cells, and markedly downregulated SMARCD1 expression. Although Smarcd1 haploinsufficient (Smarcd1+/-) male mice maintained normal serum testosterone levels, they exhibited compromised BTB integrity in testicular tissue, as evidenced by reduced expression of the junctional markers ZO-1 and Cx43 in Sertoli cells. Importantly, PA exposure further aggravated BTB disruption in Smarcd1+/- mice, reflecting the impact of Smarcd1 gene heterozygous deletion on testicular barrier vulnerability under lipid stress. Mechanistically, PA can upregulate the expression of the E3 ligase CHFR, promote ubiquitination and degradation of SMARCD1 in Sertoli cells, thereby disrupting cellular junction function and BTB stability. Together, our findings confirm SMARCD1 as a key target of PA-induced male reproductive toxicity, reveal a previously unrecognized synergistic effect of epigenetic susceptibility and environmental lipid exposure, and suggest intervention directions for maintaining male reproductive health under lipid stress conditions.