Ablation of ERO1A in tumor cells incites anti-tumor T cell immunity, promotes the efficacy of aPD-1, and induces lethal unfolded protein responses in tumor cells undergoing ER stress, enhancing anti-tumor immunity via immunogenic cell death [1]. In EGFR-mutated non-small cell lung cancer, ablating ERO1A expression affects clonogenicity, tumor sphere formation, and response to Osimertinib [2]. In SEPN1-related myopathy, ERO1A knockout in a mouse background of SEPN1 loss blunts ER stress and improves multiple MAM functions, reversing diaphragmatic weakness [3]. In Drosophila, genetic suppression or pharmacological inhibition of ERO1A homolog ERO1L provides neuroprotection under ER stress and ameliorates UBQLN2-ALS phenotypes [4]. In pancreatic ductal adenocarcinoma, inhibition of ERO1a improves monocyte infiltration and differentiation into dendritic cells [5]. In breast cancer, suppression of microglial ERO1a alleviates inflammation and enhances rehabilitative training efficacy post-ischemic stroke [6]. Small molecule-mediated inhibition of ERO1A restrains aggressive breast cancer by impairing VEGF and PD-L1 in the tumor microenvironment [8]. Cordycepin reduces ERO1A expression, inhibiting lipid metabolism and metastasis in cholangiocarcinoma [9].

In conclusion, ERO1A plays a crucial role in protein folding and redox regulation within the ER. Its ablation or inhibition in various model systems has revealed its significance in cancer, myopathy, neurodegenerative diseases, and stroke-related conditions. These model-based studies, especially gene knockout experiments, have provided insights into the potential of targeting ERO1A for therapeutic intervention in multiple disease areas.

References:

1. Liu, Lihui, Li, Sini, Qu, Yan, Ma, Zixiao, Wang, Jie. 2023. Ablation of ERO1A induces lethal endoplasmic reticulum stress responses and immunogenic cell death to activate anti-tumor immunity. In Cell reports. Medicine, 4, 101206. doi:10.1016/j.xcrm.2023.101206. https://pubmed.ncbi.nlm.nih.gov/37769655/

2. Voronkova, M A, Johnson, B, Gandhi, N, Halmos, B, Hazlehurst, L A. 2024. ERO1A levels are a prognostic indicator in EGFR mutated non small cell lung cancer. In NPJ precision oncology, 8, 250. doi:10.1038/s41698-024-00736-1. https://pubmed.ncbi.nlm.nih.gov/39496753/

3. Germani, Serena, Van Ho, Andrew Tri, Cherubini, Alessandro, Ferreiro, Ana, Zito, Ester. 2024. SEPN1-related myopathy depends on the oxidoreductase ERO1A and is druggable with the chemical chaperone TUDCA. In Cell reports. Medicine, 5, 101439. doi:10.1016/j.xcrm.2024.101439. https://pubmed.ncbi.nlm.nih.gov/38402623/

4. Yeewa, Ranchana, Sangphukieo, Apiwat, Jantaree, Phatcharida, Lo Piccolo, Luca, Jantrapirom, Salinee. 2024. ERO1A inhibition mitigates neuronal ER stress and ameliorates UBQLN2ALS phenotypes in Drosophila melanogaster. In Progress in neurobiology, 242, 102674. doi:10.1016/j.pneurobio.2024.102674. https://pubmed.ncbi.nlm.nih.gov/39395630/

5. Tay, Apple Hui Min, Cinotti, Riccardo, Sze, Newman Sui Kwan, Lundqvist, Andreas. 2023. Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma. In Frontiers in immunology, 14, 1264012. doi:10.3389/fimmu.2023.1264012. https://pubmed.ncbi.nlm.nih.gov/38187398/

6. Ren, Jing, Lv, Yuan, Tian, Qiuyan, Feng, Xing, Ding, Xin. 2023. Suppression of Microglial ERO1a Alleviates Inflammation and Enhances the Efficacy of Rehabilitative Training After Ischemic Stroke. In Molecular neurobiology, 60, 4429-4441. doi:10.1007/s12035-023-03333-8. https://pubmed.ncbi.nlm.nih.gov/37100971/

7. Shergalis, Andrea G, Hu, Shuai, Bankhead, Armand, Neamati, Nouri. 2020. Role of the ERO1-PDI interaction in oxidative protein folding and disease. In Pharmacology & therapeutics, 210, 107525. doi:10.1016/j.pharmthera.2020.107525. https://pubmed.ncbi.nlm.nih.gov/32201313/

8. Varone, Ersilia, Retini, Michele, Cherubini, Alessandro, Cantoni, Orazio, Zito, Ester. 2025. Small molecule-mediated inhibition of the oxidoreductase ERO1A restrains aggressive breast cancer by impairing VEGF and PD-L1 in the tumor microenvironment. In Cell death & disease, 16, 105. doi:10.1038/s41419-025-07426-1. https://pubmed.ncbi.nlm.nih.gov/39962052/

9. Zhou, Xuebing, Li, Yuan, Yang, Chunyu, Peng, Bosen, Ren, Xiangshan. 2023. Cordycepin reprogramming lipid metabolism to block metastasis and EMT via ERO1A/mTOR/SREBP1 axis in cholangiocarcinoma. In Life sciences, 327, 121698. doi:10.1016/j.lfs.2023.121698. https://pubmed.ncbi.nlm.nih.gov/37080351/