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Dapagliflozin, a novel antidiabetic drug, demonstrated promising effects against different disorders. Herein, we aimed to detect the dose-dependent antiarthritic impact of dapagliflozin alone and in combination with methotrexate standard treatment. Complete Freund\u2019s adjuvant-induced arthritic rats were treated with three doses of dapagliflozin (1, 5, or 10\u00a0mg\/kg\/day, p.o.) for 3 weeks, in which 10\u00a0mg dose showed eminent anti-arthritic effects according to gait score, paw diameter, arthritic index (AI), morphological and histological results. To reveal dapagliflozin mechanism, locomotor, biochemical, and histological measures were assessed in dapagliflozin (10\u00a0mg\/kg\/day) and\/or methotrexate (0.75\u00a0mg\/kg\/week, i.p.)-treated arthritic rats. Radiography and histology confirmed the prominent anti-arthritic effect of dapagliflozin via reduced RF, MMP-1, and MMP-3, and improved gait score, ankle diameter, and AI. Anti-inflammatory impact was confirmed by the downregulation of TNF-\u03b1, IL-1\u03b2, IL-6, and NF-\u03bab p65 expression. Upregulation of autophagy was detected through; Beclin-1, ULK-1, and ATG-7, in dapagliflozin treated arthritic rats. Furtherly, dapagliflozin stimulated apoptotic activity, by boosting articular levels of CASP-3, CASP-9, cartilage gene expression of p53, and Bax\/Bcl<jats:sub>2<\/jats:sub> ratio. Interestingly, dapagliflozin upregulates p-AMPK\/t-AMPK articular activity. Additionally, dapagliflozin inhibited the Hedgehog signaling pathway, through the downregulation of cartilage Shh, ptch1, Smo, and Gli-1 expression. Dapagliflozin\/methotrexate combination therapy exhibited greater anti-arthritic benefits compared to methotrexate alone. These data highlight dapagliflozin\u00a0as\u00a0an anti-rheumatic\u00a0drug,\u00a0either\u00a0alone\u00a0or with\u00a0methotrexate.<\/jats:p>","DOI":"10.1007\/s10787-025-01750-w","type":"journal-article","created":{"date-parts":[[2025,5,12]],"date-time":"2025-05-12T02:10:31Z","timestamp":1747015831000},"page":"3157-3176","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dapagliflozin targets the crosstalk between apoptosis, autophagy, and Hedgehog signaling pathways through AMPK activation in the adjuvant-induced arthritic rat model"],"prefix":"10.1007","volume":"33","author":[{"given":"Aya A.","family":"El-Demerdash","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samar F.","family":"Darwish","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marwa O.","family":"El-Derany","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2951-4892","authenticated-orcid":false,"given":"Ebtehal","family":"El-Demerdash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,12]]},"reference":[{"key":"1750_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2022.112628","volume":"147","author":"EE Abd El-Fattah","year":"2022","unstructured":"Abd El-Fattah EE, Saber S, Mourad AAE et al (2022) The dynamic interplay between AMPK\/NF\u03baB signaling and NLRP3 is a new therapeutic target in inflammation: emerging role of dapagliflozin in overcoming lipopolysaccharide-mediated lung injury. 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