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Hypertensive renal disease (HRD) is the second leading cause of end-stage renal disease (ESRD) following diabetes mellitus, with oxidative stress and inflammation serving as synergistic pathogenic drivers, the molecular mechanisms of which remain incompletely elucidated. Epigenetic regulation (especially histone methylation) is pivotal in chronic kidney disease (CKD). SMYD3, a histone methyltransferase, has been reported to modulate oxidative stress and inflammation via mediating H3K4me3 modification, while its specific role and regulatory mechanism in HRD remain largely unclear. This study explored SMYD3's function using angiotensin II (Ang II)-induced HRD models (28-day subcutaneous Ang II-infused mice in vivo; HK-2 cells in vitro). Mice were grouped into Control, HRD, HRD + MTA (an H3K4 methylation inhibitor), BCI-121 (a SMYD3 inhibitor), and HRD + BCI-121. In vivo, blood, urine, and kidney samples were analyzed via biochemical assays (creatinine, BUN, oxidative stress biomarkers) and histopathology (HE, PAS, Masson staining). In vitro, SMYD3 was inhibited by BCI-121 or siRNA, with Western blotting, co-IP, and ChIP detecting interactions among SMYD3, H3K4me3, TXNIP promoter, and JAK2/STAT3 pathway-related molecules. Ang II infusion aggravated renal dysfunction (elevated creatinine, BUN, urinary albumin), pathological damage, oxidative stress, inflammation, and cellular senescence, accompanied by increased SMYD3 and H3K4me3. Treatment with MTA/BCI-121 alleviated these changes, and SMYD3 knockdown/inhibition reversed Ang II-induced injuries in HK-2 cells. Mechanistically, SMYD3 was associated with enhanced TXNIP transcription via H3K4me3 methylation, activating NLRP3 inflammasome and oxidative stress pathways. SMYD3 was regulated by the JAK2/STAT3 pathway; STAT3 inhibitor S3I-201 reduced SMYD3 and H3K4me3, indicating that JAK2/STAT3 upregulates SMYD3 to exacerbate HRD. In conclusion, our findings demonstrate that SMYD3 acts as a key responsive mediator of Ang II-induced renal oxidative stress and inflammation, which is closely associated with the promotion of H3K4me3 enrichment at the TXNIP promoter. We also identify that the Ang II-activated JAK2/STAT3 axis may function as an upstream regulator of SMYD3 expression, thus providing novel insights and potential therapeutic targets for HRD.