BACKGROUND: Intervertebral disc degeneration (IDD) is integral in lower back pain and involves complex pathophysiological processes, including nucleus pulposus (NP) cell apoptosis and extracellular matrix (ECM) breakdown. Palmatine (PLT), an isoquinoline alkaloid extracted from Fibraurea recisa Pierre of the family Menispermaceae, is recognised for its anti-inflammatory, antioxidant, and neuroprotective effects. Nevertheless, researches have not well explored the impact of PLT on IDD. OBJECTIVE: This investigation aimed at determining the impact of PLT on oxidative stress caused by tert‑butyl hydroperoxide (TBHP) and exploring its potential as a therapeutic agent and its mechanisms in IDD. METHODS: Potential anti-IDD targets of PLT were identified using network pharmacology and bioinformatics methods and evaluated using Gene Ontology analysis. The method of molecular docking helped elucidate the interaction mode and connections between PLT and transcription factor EB (TFEB). Cellular thermal shift assays and cycloheximide chase experiments confirmed direct interactions between PLT and TFEB. NP cell apoptosis, ECM levels, endoplasmic reticulum stress (ERS), autophagy, and TFEB expression were evaluated using western blotting, TUNEL staining, EdU staining, flow cytometry, immunofluorescence, and alcian blue staining. Functional IDD recovery was evaluated using MRI and X-ray, haematoxylin-eosin (HE) staining, safranin O/fast green staining, and immunohistochemical (IHC) staining. Moreover, needle puncture was used to establish an in vivo rat model of IDD to examine the therapeutic efficacy of PLT. RESULTS: PLT markedly mitigated ERS and inhibited TBHP-induced ECM degradation and NP cell apoptosis by activating TFEB and upregulating autophagy. In the IDD rat model, PLT improved annulus fibrosus (AF) and NP morphology and structure. CONCLUSION: These findings demonstrate that PLT alleviates IDD progression by upregulating TFEB
therefore, TFEB represents a potential novel therapeutic target. Moreover, this study reveals for the first time that PLT inhibits ERS by enhancing TFEB-mediated autophagy, thereby reducing NP cell apoptosis and ECM degradation, thus providing valuable insights into the key pharmacological mechanisms of PLT.