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Nevertheless, the precise molecular mechanisms underlying this phenomenon remain unclear, and effective treatment strategies are scarce. This study explored the protective effects of ellagic acid (EA), a natural polyphenolic compound, against CdSO4 exposure-induced neurotoxicity in HT22 cells and the underlying molecular mechanisms. Our findings demonstrated that exposure of HT22 cells to CdSO4 resulted in apoptosis, which was effectively reversed by EA in a dose-dependent manner. EA supplementation also decreased reactive oxygen species (ROS) and mitochondrial ROS production, reduced malondialdehyde (MDA) levels, and restored the activities of superoxide dismutase (SOD) and catalase (CAT). Additionally, EA supplementation at 5\u201320 \u03bcM significantly counteracted Cd-induced the loss of mitochondrial membrane potential and the decrease of ATP and reduced the ratio of Bax\/Bcl-2 and cleaved-caspase-3 protein expression. Furthermore, EA supplementation resulted in the upregulation of Nrf2 and HO-1 protein and mRNAs while simultaneously downregulating the phosphorylation of JNK and p38 proteins. The pharmacological inhibition of c-Jun N-terminal kinase (JNK) partially attenuated the activation of the Nrf2\/HO-1 pathway induced by CdSO4 and exacerbated its cytotoxic effects. In conclusion, our findings suggest that ethyl acetate (EA) supplementation offers protective effects against CdSO4-induced apoptosis in HT22 cells by inhibiting oxidative stress and activating the Nrf2 signaling pathway. Furthermore, the activation of the JNK pathway appears to play a protective role in CdSO4-induced apoptosis in HT22 cells.<\/jats:p>","DOI":"10.3390\/antiox13111296","type":"journal-article","created":{"date-parts":[[2024,10,25]],"date-time":"2024-10-25T08:42:13Z","timestamp":1729845733000},"page":"1296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Ellagic Acid Reduces Cadmium Exposure-Induced Apoptosis in HT22 Cells via Inhibiting Oxidative Stress and Mitochondrial Dysfunction and Activating Nrf2\/HO-1 Pathway"],"prefix":"10.3390","volume":"13","author":[{"given":"Yue","family":"Liu","sequence":"first","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"},{"name":"Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Chen","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9516-6270","authenticated-orcid":false,"given":"Zhihui","family":"Hao","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"},{"name":"Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianzhong","family":"Shen","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"},{"name":"Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shusheng","family":"Tang","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"},{"name":"Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4677-0524","authenticated-orcid":false,"given":"Chongshan","family":"Dai","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Veterinary Public Health and Safety, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"},{"name":"Technology Innovation Center for Food Safety Surveillance and Detection (Hainan), Sanya Institute of China Agricultural University, Sanya 572025, China"},{"name":"Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159950","DOI":"10.1016\/j.scitotenv.2022.159950","article-title":"Long-term cadmium exposure impairs cognitive function by activating lnc-Gm10532\/m6A\/FIS1 axis-mediated mitochondrial fission and dysfunction","volume":"858","author":"Deng","year":"2023","journal-title":"Sci. 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