Mesenchymal stem cells-derived miR-143-3p attenuate acute kidney injury by suppressing TAK1-Driven necroptosis

Cisplatin, a widely used chemotherapeutic agent, induces nephrotoxicity with approximately 30 % of patients developing acute kidney injury (AKI). Necroptosis, a regulated cell death pathway driven by RIPK1/RIPK3/MLKL activation, plays a pivotal role in cisplatin-induced AKI, yet effective therapeutic strategies targeting this pathway remain limited. Here, we demonstrate that human umbilical cord mesenchymal stem cells (huc-MSCs) alleviate cisplatin-induced AKI by suppressing necroptosis through targeting transforming growth factor-β-activated kinase 1 (TAK1). In cisplatin-treated mice, huc-MSCs significantly reduced renal dysfunction (lower serum creatinine and urea nitrogen), attenuated tubular injury (decreased KIM-1 expression), and mitigated inflammatory responses (reduced TNF-α, IL-6, and macrophage infiltration). Mechanistically, huc-MSCs inhibited the cisplatin-induced phosphorylation of RIPK1/RIPK3/MLKL of the necroptosis pathway, while downregulating TAK1 expression and activity in renal tissues and tubular epithelial cells (HK-2). Overexpression of TAK1 abolished the protective effects of huc-MSCs to inhibit necroptosis, indicating that huc-MSCs alleviate necroptosis by inhibiting TAK1. Further studies identified miR-143-3p, a highly expressed miRNA in huc-MSCs, as the key mediator targeting TAK1 mRNA via direct binding, thereby suppressing TAK1-driven necroptosis, whereas inhibition of miR-143-3p reversed their ability to attenuate renal injury, inflammation, and necroptosis in vivo. This study elucidates a novel mechanism by which huc-MSCs exert renoprotection through the miR-143-3p/TAK1 axis-mediated inhibition of necroptosis, offering a promising strategy for clinical AKI management.