Background and Purpose: Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by using herbal medicines. Currently, no therapies are available to treat or prevent AAN. Histone deacetylase (HDAC) plays a crucial role in the development and progression of renal disease. We tested whether HDAC inhibitors could prevent AAN and determined the underlying mechanism. Experimental Approach: HDACs expression in the kidneys was examined. Mouse kidney and renal tubular epithelial cell damage were assessed after exposure to HDAC1 and HDAC2 blockade (FK-228). Conditional knock-in of Proline-serine-threonine-phosphatase-interacting protein 2 (PSTPIP2) in the kidney and knockdown of PSTPIP2 expression in PSTPIP2-knockin mice, pathological parameters, and kidney injuries were assessed. Key Results: Aristolochic acid upregulated the expression of HDAC1 and HDAC2 in the kidneys. Notably, the HDAC1 and -2 specific inhibitor, romidepsin (FK228, Depsipeptide), suppressed aristolochic acid-induced kidney injury, epithelial cell pyroptosis, apoptosis, and necroptosis (PANoptosis). Moreover, romidepsin upregulated PSTPIP2 in renal tubular epithelial cells, which was enhanced by aristolochic acid treatment. Conditional knock-in of PSTPIP2 in the kidney protected against AAN. In contrast, the knockdown of PSTPIP2 expression in PSTPIP2-knockin mice restored kidney damage and PANoptosis. PSTPIP2 function was determined in vitro using PSTPIP2 knockdown or overexpression in mTEC. Additionally, PSTPIP2 was found to regulate Caspase-8 in Aristolochic acid nephropathy. Conclusion and Implications: HDAC-mediated silencing of PSTPIP2 may contribute to aristolochic acid nephropathy. Hence, HDAC1 and -2 specific inhibitors or PSTPIP2 could be valuable therapeutic agents for the prevention of aristolochic acid nephropathy.