Untargeted metabolomics reveals Syzygium cumini (L.) alleviates ER stress and redox damage via activation of ATF-6/CHOP/NF-κB signaling axis in diabetic rats.

UNLABELLED: This study reports the therapeutic potential of aqueous seed extract Syzygium cumini (AESC) in alleviating type 1 diabetes mellitus (T1DM) associated endoplasmic reticulum (ER) and oxidative stress in a streptozotocin (STZ)-induced rat model. The LC-MS/MS analysis of AESC revealed gallic acid, ellagic acid, quercetin, malic acid, and citric acid as major antidiabetic phytoconstituents. Administration of AESC (250 mg/kg) normalized fasting blood glucose levels to those of healthy control rats. Moreover, AESC increases antioxidant levels and downregulates ER and inflammatory markers. Histopathological evaluation showed improved pancreatic tissue architecture, and immunohistochemistry revealed enhanced insulin expression within the islets. Mechanistically, AESC alleviated ER stress and oxidative damage through the ATF-6/CHOP/NF-κB signaling axis. Furthermore, serum metabolomics indicated aberrant accumulation of branched-chain amino acids and reduced 3-hydroxybutyrate levels (increased ketolysis) in diabetic rats that were reversed by AESC. This study is limited by using a single dosage of AESC and short-term evaluation, emphasizing acute rather than long-term effects. Furthermore, the lack of in vitro validation and genetic knockdown approaches restricts confirmation of the specific mechanisms underlying the antidiabetic action of the extract. Future studies employing multiple dosage regimens, chronic treatment models, and molecular validation strategies are warranted to establish the long-term efficacy, safety, and mechanistic specificity of AESC as a potential therapeutic for T1DM.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-025-04523-y.