A novel MST1-targeting kinsenoside derivative K30 attenuates acute kidney injury by restoring mitochondrial homeostasis

Acute kidney injury (AKI) is a heterogeneous syndrome with limited treatments, underscoring the need for new therapies. The natural glycoside kinsenoside is a promising candidate owing to its anti-inflammatory and antioxidant properties. We synthesized a series of kinsenoside derivatives and identified K30 as the most effective nephroprotective compound. In murine models of cisplatin-, folic acid-, and ischemia-reperfusion-induced AKI, K30 significantly preserved renal function, attenuated inflammation and oxidative stress, ameliorated mitochondrial dysfunction, and showed no evident systemic toxicity. Cellular thermal shift assay combined with mass spectrometry identified mammalian STE20-like kinase 1 (MST1) as the direct target of K30, which was further validated by drug affinity responsive target stability assays, molecular docking, surface plasmon resonance and in vitro kinase activity assays. The renoprotective effect of K30 was abolished in MST1-knockdown cells and restored upon MST1 re-expression, and its efficacy was comparable to two established MST1 inhibitors. Mechanistically, K30 exerts its renoprotective effect by directly targeting and inhibiting MST1, thus suppressing the downstream JNK–Drp1 signaling axis, which in turn ameliorates pathological mitochondrial fission. These results demonstrate that K30 is an effective MST1-targeting compound capable of maintaining mitochondrial homeostasis, highlighting its potential as a novel therapeutic agent for AKI. By targeting MST1, K30 restored mitochondrial homeostasis in AKI, which led to a cascade of improvements including suppressed mitochondrial fission, preserved structural and functional integrity, and ultimately attenuated oxidative stress and inflammation.