Pancreatic β-cell apoptosis caused by apolipoprotein C3-rich low-density lipoprotein is attenuated by kansuinine A through oxidative stress inhibition

Dyslipidemia exacerbates pancreatic β-cell apoptosis, heightening the risk of type 2 diabetes (T2DM). Kansuinine A (KA), a diterpene from Euphorbia roots, exhibits antiapoptotic properties, suggestive of its therapeutic potential against T2DM. In this study, we evaluated the protective effects of KA against apolipoprotein C3 (ApoC3)-rich low-density lipoprotein (LDL) (AC3RL)-induced β-cell apoptosis and its underlying mechanism of action. ApoE^-/- mice fed a high-fat diet and treated with KA demonstrated improved glucose and insulin tolerance, enhanced antioxidant capacity, and reduced pancreatic β-cell apoptosis. In rat pancreatic β-cells (RIN-m5F) exposed to AC3RL, KA significantly improved cell viability, suppressed oxidative stress, and mitigated apoptosis by downregulating lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) expression and inhibiting the IκB kinase β (IKKβ)/Inhibitor of κB alpha (IκB⍺)/Nuclear Factor kappa B(NF-κB) signaling pathway. Molecular docking and pathway analyses revealed the interactions of KA with key targets involved in oxidative stress and apoptosis. These findings highlight the ability of KA to counteract AC3RL-induced β-cell dysfunction, offering promise as a potential intervention for dyslipidemia-driven diabetes.