ACSL4 inhibition alleviates elevated ATRA-driven spermatogenic damage in chronic colitis with gut microbiota dysbiosis

Chronic colitis is a prevalent, manageable yet incurable disorder whose extraintestinal manifestations impair male reproductive health. However, the primary mechanisms underlying these effects, their molecular targets, and effective mitigation strategies remain largely unclear. The present study employed 16 S rRNA sequencing and untargeted metabolomics, revealing that colitis-induced gut microbiota leads to abnormal elevation of all-trans retinoic acid (ATRA). The RNA-seq results showed that the circulating abnormally elevated ATRA triggers alterations of testicular lipid metabolism, inducing upregulation of ACSL4 in both germ cells and somatic cells, thereby initiating a lipid peroxidation cascade. This process culminates in the accumulation of MDA, ultimately impairing spermatogenesis. Targeted inhibition of ACSL4 using AS252424 significantly suppresses its expression in the testes and reduces MDA levels, thereby alleviating spermatogenic impairment. The present work offers new perspectives and theoretical foundations for mitigating reproductive damage caused by chronic colitis.