HIF1α/SMYD2/STAT3 axis drives partial EMT and renal fibrosis in cisplatin-induced CKD

Cisplatin-induced nephrotoxicity remains a serious clinical complication that can progress to chronic kidney disease (CKD) and renal fibrosis. Partial epithelial–mesenchymal transition (pEMT) in renal tubular epithelial cells (RTECs) is a key process in fibrosis progression, yet the underlying regulatory mechanisms are not fully understood. This study aimed to investigate whether SMYD2, a lysine methyltransferase, promotes pEMT and renal fibrosis via methylation and activation of STAT3. We utilized a repeated low-dose cisplatin model to induce CKD in mice and treated HK-2 cells with cisplatin in vitro. Genetic knockdown and pharmacological inhibition (LLY507) of SMYD2 were employed, along with overexpression and pharmacological inhibition strategies for HIF1α and STAT3. Techniques included co-immunoprecipitation, Western blot, immunofluorescence, immunohistochemistry, luciferase reporter assays, ChIP-qPCR, and analysis of human CKD transcriptomic data from the Nephroseq database. SMYD2 was significantly upregulated in human CKD samples, cisplatin-treated mice, and HK-2 cells. We identified HIF1α as a direct transcriptional regulator of SMYD2 under cisplatin-induced stress. SMYD2 bound to and methylated STAT3 at lysine 685, facilitating its phosphorylation at tyrosine 705 and promoting nuclear translocation. Activation of this SMYD2–STAT3 axis drove pEMT, inflammatory cytokine secretion, and extracellular matrix deposition. Inhibition of SMYD2 attenuated STAT3 activation, suppressed pEMT and fibrosis. Our study reveals a novel mechanism by which SMYD2-mediated methylation of STAT3 promotes pEMT and renal fibrosis in cisplatin-induced CKD. Targeting the HIF1α/SMYD2/STAT3 signaling axis may offer a promising therapeutic strategy to mitigate cisplatin-induced kidney injury while potentially enhancing chemotherapeutic efficacy.