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While expression of the S protein in human cells can induce the accumulation of reactive oxygen species (ROS), the regulatory mechanisms governing this process remain poorly understood. Here, we identify the human protein HCLS1\u2010associated protein X\u20101 (HAX1) as a key regulator that mitigates SARS\u2010CoV\u20102S\u2010induced ROS accumulation. A genome\u2010wide screen revealed HAX1 as a binding partner of the SARS\u2010CoV\u20102S protein in mammalian cells. HAX1 specifically interacts with the S1 subunit of S, and its deficiency effectively abolishes S\u2010induced activation of endoplasmic reticulum (ER) stress responses, including the unfolded protein response (UPR). Notably, HAX1\u2010dependent UPR activation is unique to SARS\u2010CoV\u20102S and certain variants and is not triggered by other UPR inducers. Loss of HAX1 markedly exacerbates SARS\u2010CoV\u20102S\u2010induced ROS accumulation and mitochondrial dysfunction. Collectively, our findings uncover a previously unrecognized mechanism by which S modulates host stress responses and establish HAX1 as a host factor involved in SARS\u2010CoV\u20102\u2010related processes.<\/jats:p>","DOI":"10.1111\/febs.70163","type":"journal-article","created":{"date-parts":[[2025,6,26]],"date-time":"2025-06-26T07:14:33Z","timestamp":1750922073000},"page":"5948-5964","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>HAX1<\/scp>\n                    mediates\n                    <scp>SARS<\/scp>\n                    \u2010\n                    <scp>CoV<\/scp>\n                    \u20102 spike\u2010triggered unfolded protein response in host cells"],"prefix":"10.1111","volume":"292","author":[{"given":"Fang","family":"Zhu","sequence":"first","affiliation":[{"name":"School of Medicine Guizhou University  Guiyang 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