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Current evidence shows that TNF\u2010\u03b1 maturation, co\u2010translational and post\u2010modifications, ER\u2010luminal folding and trimerisation, Golgi trafficking, and ectodomain shedding by ADAM17 are constrained by ER chaperones and ER\u2010associated degradation (ERAD). Furthermore, TNF\u2010\u03b1 signalling reciprocally interfaces with the proteostasis network (PN) largely through inflammatory stress pathways such as NF\u2010\u03baB\u2010dependent transcriptional control of chaperones, ubiquitin\u2010proteasome components, and autophagy regulators. However, dysregulation of this bidirectional crosstalk mechanistically contributes to disease, including chronic inflammatory disorders, cancer, and degenerative diseases. In this study we provide a synthesis of the current literature on pathways related to protein homeostasis control that determines whether TNF\u2010\u03b1 exposure is adaptive or proteotoxic. We also discuss the translational implications this could have by including rational combinations of TNF\u2010\u03b1 targeted blockers with PN modulators (chemical chaperones, proteasome or autophagy modulators), which reduce the proteotoxic burden. Therefore, understanding the crosstalk between TNF\u2010\u03b1 signalling and components of the PN system promises new mechanistic insights and translational targets for TNF\u2010\u03b1\u2010driven diseases.<\/jats:p>","DOI":"10.1111\/febs.70553","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T11:39:43Z","timestamp":1777117183000},"page":"5645-5663","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Biogenesis of\n                    <scp>TNF<\/scp>\n                    \u2010\u03b1\u2010insights into proteostasis and inflammation"],"prefix":"10.1111","volume":"293","author":[{"given":"Bailasan","family":"Haidar","sequence":"first","affiliation":[{"name":"INSERM U1242, University of Rennes  France"},{"name":"First Faculty of Medicine, BIOCEV, Charles University  Vestec\u2010Prague 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