Lyn attenuates cisplatin-induced acute kidney injury by inhibition of RIPK1-mediated apoptosis and necroptosis.

Cisplatin-induced acute kidney injury (CP-AKI) often limits its clinical utility in treating various solid tumors. However, the underlying pathogenesis of CP-AKI is still unclear. Lyn, a member of Src family kinases, is predominantly implicated in regulating immune response and inflammation. This study investigates the functional role of Lyn in CP-AKI, as well as the possible mechanism. Here, we found that Lyn was down-regulated in mice with CP-AKI. Knockout of Lyn exacerbated renal damage, increased inflammatory cytokine expression, and promoted tubular cell apoptosis and necroptosis in the kidneys of CP-AKI mice. Conversely, both Lyn agonist MLR-1023 and RIPK1 inhibitor Necrostatin-1 (Nec-1) attenuated cisplatin-triggered kidney injury, tubular cell apoptosis and necroptosis. Moreover, in vitro study showed that Lyn knockout/knockdown aggravated cisplatin-induced apoptosis and necroptosis in renal tubular epithelial cells, while Lyn overexpression alleviated them. Mechanistically, Lyn interacted with RIPK1 and inhibited the phosphorylation activation of RIPK1. In conclusion, our study revealed that Lyn protects from cisplatin-induced nephrotoxicity by suppressing RIPK1-mediated apoptosis, necroptosis and inflammation. Thus, Lyn kinase may serve as a promising therapeutic target for CP-AKI.