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During infection, Mycobacterium tuberculosis (Mtb) induces ferroptosis, an iron-induced mode of cell death, that aids in dissemination and survival. Here, we identify a functional role for activin A and the downstream mothers against decapentaplegic homolog (SMAD) 2\/3 signaling in Mtb-induced ferroptosis and disease progression. Molecular assays, including chromatin immunoprecipitation and loss-of-function analysis, demonstrated that activin A regulates the expression of KAT8, which in turn regulates levels of heme oxygenase (HO-1). Mechanistically, we identify that KAT8-mediated acetylation of nuclear factor erythroid 2\u2013related factor (NRF2) during Mtb infection enhances its nuclear availability leading to increased HO-1 expression. Finally, using an in vivo mouse model of tuberculosis, we show that the pharmacological inhibition of activin A receptor and KAT8 restricts Mtb burden, limits dissemination and ameliorates tuberculosis pathology. Thus, we report a novel role for activin A in regulating NRF2 localization and outline its potential consequences during tuberculosis.<\/jats:p>","DOI":"10.1093\/infdis\/jiaf482","type":"journal-article","created":{"date-parts":[[2025,9,14]],"date-time":"2025-09-14T11:38:39Z","timestamp":1757849919000},"page":"307-318","source":"Crossref","is-referenced-by-count":3,"title":["Role of Activin A\u2013Mediated KAT8 Expression in Regulating Ferroptosis During\n                    <i>Mycobacterium tuberculosis<\/i>\n                    Infection"],"prefix":"10.1093","volume":"233","author":[{"given":"Bijewar Ashish","family":"Satish","sequence":"first","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science , Bengaluru, Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Smriti","family":"Sundar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science , Bengaluru, Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raju S","family":"Rajmani","sequence":"additional","affiliation":[{"name":"Molecular Biophysics Unit, Indian Institute of Science , Bengaluru, Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kithiganahalli Narayanaswamy","family":"Balaji","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Cell Biology, Indian Institute of Science , Bengaluru, Karnataka ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"2026031304543301500_jiaf482-B1","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1146\/annurev-immunol-032712-095939","article-title":"The immune response in tuberculosis","volume":"31","author":"O\u2019Garra","year":"2013","journal-title":"Annu Rev 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