{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T06:47:43Z","timestamp":1782110863907,"version":"3.54.5"},"reference-count":52,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Limb ischemia\u2010reperfusion (I\/R) injury is a life\u2010threatening complication of acute limb ischemia that can result in severe skeletal muscle damage and limb loss, yet effective pharmacological therapies remain limited. Kaempferol (KAE), a naturally occurring dietary flavonoid with well\u2010documented anti\u2010inflammatory, antioxidant, and anti\u2010apoptotic properties, has been shown to confer protection in myocardial and cerebral I\/R models. Nevertheless, its therapeutic potential and molecular mechanisms in limb I\/R injury have not yet been elucidated. In this study, we systematically investigated the protective effects and underlying mechanisms of KAE in a mouse hindlimb I\/R model. A network pharmacology approach was initially applied to provide a global overview of potential biological processes associated with KAE treatment. The therapeutic efficacy and molecular mechanisms of KAE were subsequently evaluated using in vivo experiments combined with transcriptomic profiling. Mice subjected to 4\u2009h of hindlimb ischemia followed by 24\u2009h of reperfusion received KAE (50 or 100\u2009mg\/kg, intraperitoneally) for 7 consecutive days prior to I\/R induction. KAE markedly improved hindlimb microcirculation, alleviated tissue edema and infarction, preserved muscle histological integrity, and attenuated elevations of circulating muscle injury biomarkers. In parallel, KAE significantly suppressed I\/R\u2010induced oxidative stress, inflammatory infiltration, and apoptotic cell death, as evidenced by reduced ROS accumulation, decreased pro\u2010inflammatory cytokine expression, and favorable modulation of apoptosis\u2010related proteins. Transcriptomic analysis revealed pronounced activation of inflammatory pathways and suppression of the PPAR signaling pathway following limb I\/R injury, whereas KAE treatment selectively restored PPAR pathway activity while inhibiting NF\u2010\u03baB signaling. qRT\u2010PCR and Western blot analyses further demonstrated that KAE predominantly upregulated PPAR\u03b1 expression and reduced NF\u2010\u03baB p65 phosphorylation in reperfused skeletal muscle. Collectively, these findings provide comprehensive evidence that KAE protects against hindlimb I\/R injury, with activation of PPAR\u03b1 signaling and concomitant suppression of NF\u2010\u03baB\u2010driven inflammation representing a proposed mechanism, thereby supporting KAE as a promising pharmacological candidate for limb I\/R injury.<\/jats:p>","DOI":"10.1002\/jbt.70914","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T06:17:42Z","timestamp":1779171462000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Kaempferol Protects Against Hindlimb Ischemia\u2010Reperfusion Injury via Activation of PPAR\u03b1 Signaling"],"prefix":"10.1002","volume":"40","author":[{"given":"Yuehe","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Jinling Clinical Medical College Nanjing University of Chinese Medicine Nanjing China"},{"name":"Department of 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