Thinned young apple polyphenol mitigates palmitic acid-induced neuronal injury by upregulating TET2 in primary hippocampal neurons

Purpose: Thinned young apple polyphenol (TYAP) has demonstrated neuroprotective effects, likely by enhancing mitochondrial function through the involvement of 5-hydroxymethylcytosine (5hmC) levels and the ten-eleven translocation (TET) enzymes. This study aimed to evaluate whether TYAP restores mitochondrial function and 5hmC levels in a palmitic acid (PAL)-induced hippocampal injury model. Approach: Palmitic acid (PAL)-induced hippocampal injury was prepared in primary hippocampal neurons, and the TYAP treatments with different doses (50–200 μg/mL) were also applied. The neurons were randomly assigned to 6 groups: Control, Control + TYAP (200 μg/mL), PAL, PAL + TYAP (50 μg/mL), PAL + TYAP (100 μg/mL), and PAL + TYAP (200 μg/mL). Outcomes, including measures of inflammation, oxidative stress, apoptosis, mitochondrial function, and DNA epigenetic changes (such as 5hmC and 5 mC), were assessed. Additionally, the effects of TYAP were evaluated in TET2-knockdown HT22 cells to assess the involvement of TET2 in TYAP treatment. Results: TYAP mitigated PAL-induced hippocampal injury by restoring TET2 and 5hmC levels, reducing oxidative stress, inflammation, and apoptosis, and enhancing mitochondrial function. Knockdown of TET2 abolished these effects, demonstrating the critical role of TET2 in TYAP-mediated neuroprotection. Conclusions: TYAP confers neuroprotection against PAL-induced hippocampal neuron damage through the TET2-5hmC pathway, highlighting its potential as a therapeutic agent for neurological conditions associated with mitochondrial dysfunction and apoptosis. © 2025 The Authors