TNFAIP1 Facilitates the Progression of Diabetic Cardiomyopathy Through the p38 MAPK ‐Mediated ER Stress‐Apoptosis Axis

ABSTRACT Diabetic cardiomyopathy (DCM), a diabetes‐specific myocardial pathology, is a significant contributor to diabetes‐related heart failure. Endoplasmic reticulum (ER) stress plays a crucial role in DCM, yet its upstream regulatory mechanisms remain incompletely elucidated. Cellular heterogeneity in DCM was investigated by analyzing single‐cell transcriptomic data from the Gene Expression Omnibus. A mouse DCM model was established and validated using echocardiography, serum biochemical assays, and histological analysis. TNFAIP1 expression was detected by Western blot. A high glucose‐induced DCM cellular model was constructed using HL‐1 cardiomyocytes and neonatal cardiomyocytes (NMCMs). Cell injury and TNFAIP1 expression were assessed via TUNEL staining, Annexin V/PI staining, CellRox probe, RT‐qPCR, and Western blot. Finally, a TNFAIP1‐knockdown DCM mouse model was constructed, and the in vitro results were further validated by echocardiography, serum biochemical assays, histological analysis, and other methods. Single‐cell analyses revealed the enrichment of TNFAIP1 + cardiomyocytes in DCM, with their differentially expressed genes enriched in p38 MAPK and apoptosis signaling pathways. TNFAIP1 expression was significantly upregulated in both DCM mouse and cellular models. TNFAIP1 overexpression activated p38 MAPK‐mediated ER stress, increased ROS levels, and promoted apoptosis, whereas TNFAIP1 knockdown produced the opposite effects. These effects were significantly reversed by the p38 MAPK pathway inhibitor SB203580, the ER stress inhibitor TUDCA, and the ER stress inducer Thapsigargin. Finally, in vivo experiments further confirmed that TNFAIP1 knockdown ameliorated the progression of myocardial injury in DCM mice. TNFAIP1 promotes DCM progression via the p38 MAPK‐mediated ER stress‐apoptosis axis, identifying TNFAIP1 as a novel potential therapeutic target for DCM.