Extracellular vesicles carrying miR-143-3p released from Sertoli cells drives age-related decline of testosterone and male fertility

Abstract As delayed parenthood becomes more prevalent, understanding age-related testosterone decline and its impact on male fertility has gained importance. However, molecular mechanisms concerning testicular aging remain largely undiscovered. Our study highlights that miR-143-3p, present in aging Sertoli cells (SCs), is discharged into extracellular vesicles (EVs), affecting Leydig cells (LCs) and germ cells, thus disrupting testicular tissue homeostasis and spermatogenesis. Intriguingly, in SCs, TGF-β signaling promotes miR-143 precursors transcription, increasing mature miR-143-3p levels. This inhibits Smurf2, activating Smad2, and further enhancing miR-143-3p accumulation. EVs transporting miR-143-3p, originating from SCs, contribute to the age-related decline of testosterone and male fertility by targeting the luteinizing hormone receptor and retinoic acid receptor. Diminishing endogenous miR-143-3p in SCs postpones testis aging, preserving and prolonging male fertility. Thus, our study identified miR-143 as a key regulator of testicular function and fertility, revealing miR-143 as a potential therapeutic target for male abnormal sexual and reproductive function.