The aim of this study was to evaluate for the effects of forsythiaside A (FA) on myocardial injury in streptozotocin (STZ)-induced diabetes mice. Blood glucose (BG), serum triglycerides (TG), lactate dehydrogenase (LDH), creatine kinase isoenzyme (CK-MB), cardiac troponin (cTnI), malondialdehyde (MDA), superoxide dismutase (SOD) levels were detected in STZ mice. The structure and function of heart was observed via cardiac ultrasound. Cytokine levels in mouse serum and heart were detected using enzyme-linked immunosorbent assay (ELISA) as well as TG, LDH, CK-MB, cTnI, MDA and SOD in high glucose (Glu) induced H9c2 cells. Western blot detection of the expression of endoplasmic reticulum stress-related TXNIP/NLRP3 inflammasome pathways (GRP78, PERK, P-PERK, EIF-α, P-EIF-α, XBP1, ATF6, TXNIP and NLRP3) in SCD mice and LCG induced H9c2 cells. Endoplasmic reticulum stress activator tunicamycin (TM) was used to validate the above pathway for FA. It was also found that FA had protective effects on myocardial injury in STZ mice via restored heart function, improved cardiac pathological changes and suppressed inflammatory response as well as in Glu induced H9c2 cells. In conclusion, FA alleviated myocardial injury in diabetes via endoplasmic reticulum stress-NLRP3 inflammasome pathway.Copyright © 2024 Elsevier B.V. All rights reserved.