{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T10:31:26Z","timestamp":1786444286247,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FEBS Journal"],"abstract":"<jats:p>\n                    Heat shock factor 1 (HSF1) masters cellular proteostasis under stress by upregulating molecular chaperones that help refold or degrade misfolded proteins. HSF1 activation involves its monomer\u2010to\u2010oligomer transition and binding to its recognition sequence: the heat shock elements (HSEs) on its target gene promoters. HSF1 activity declines with age as well as in neurodegenerative disorders (NDs) such as Parkinson's disease, highlighting the need for therapeutic strategies to restore its function. Azadiradione (AZD), a limonoid isolated from\n                    <jats:italic>Azadirachta indica<\/jats:italic>\n                    seeds, directly activates HSF1 in cellular and preclinical ND models, unlike other small\u2010molecule activators reported elsewhere. In this study, the molecular basis of AZD\u2010mediated HSF1 activation was investigated using purified variants of HSF1, including those lacking its oligomerization and transactivation domains. Fluorescence polarization and dynamic light scattering assays revealed that AZD promotes the oligomerization of monomeric HSF1 to enhance its HSEs\u2010binding affinity by engaging its DNA\u2010binding domain (DBD). The oligomerization domain, which is required for stress\u2010induced HSF1 activation, appears redundant in AZD\u2010mediated activation. Furthermore, evidence suggests that AZD\u2010induced conformational alterations in the HSEs\u2010DNA facilitate its binding to the HSF1 monomer. Intriguingly, AZD was found to compromise the DNA\u2010binding ability of pre\u2010assembled trimeric\/oligomeric HSF1. This finding also highlighted a potential anticancer effect of AZD, as cancer cells heavily depend on this HSF1 population for rapid proliferation and survival. Overall, these findings offer new insights into the functional regulation of HSF1 and suggest a framework for developing small\u2010molecule HSF1 activators with therapeutic potential for protein conformational disorders.\n                  <\/jats:p>","DOI":"10.1111\/febs.70677","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T09:45:21Z","timestamp":1786441521000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Azadiradione regulates heat shock factor 1 function by interacting with its\n                    <scp>DNA<\/scp>\n                    \u2010binding domain independent of the oligomerization domain"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4457-2174","authenticated-orcid":false,"given":"Anirban","family":"Manna","sequence":"first","affiliation":[{"name":"Division of Molecular Medicine Bose Institute  Kolkata 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