Abstract

Locoweed toxicity (locoism) is a severe toxicological disorder in grazing livestock, primarily caused by swainsonine (SW), an indolizidine alkaloid that inhibits α-mannosidase, disrupts glycoprotein processing, and induces endoplasmic reticulum stress (ERS), unfolded protein response (UPR) activation, and dysregulated autophagy, leading to multi-organ damage, particularly in the kidney. Despite reported anticancer and immunomodulatory activities, the high toxicity of SW limits its biological application, and effective protective strategies remain unavailable. Lycopene (LYC), a natural carotenoid with potent antioxidant properties, has been shown to regulate ERS and autophagy. This study investigated the protective effects of LYC against SW-induced cellular stress and the underlying mechanisms related to ERS and UPR signaling. Primary rat renal tubular epithelial cells (RTECs) were treated with SW with or without LYC, and autophagy and ERS-related responses were analyzed using Western blotting, RT-qPCR, immunofluorescence, and Ad-GFP-mCherry-LC3 assays. The results demonstrated that 10 μM LYC significantly attenuated SW-induced autophagy, as evidenced by decreased LC3-II/LC3-I and p62 protein levels, without markedly altering autophagy-related gene transcription. Additionally, LYC partially suppressed SW-induced ERS by reducing p-eIF2α and ATF4 expression, while the IRE1α and ATF6 pathways were largely unaffected. In conclusion, lycopene partially alleviates SW-induced autophagy in renal tubular epithelial cells, likely through modulation of PERK-dependent UPR signaling, providing experimental evidence for its potential protective role against locoweed toxicity.