ReviewFrontiers in pharmacology2026
Multidimensional targeting of ischemia-reperfusion injury by genistein: from molecular crosstalk to clinical translation.
Review in Frontiers in pharmacology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
Ischemia-reperfusion injury (IRI) is a convergent pathology driven by oxidative stress, sterile inflammation, mitochondrial dysfunction, and regulated cell death (apoptosis, necroptosis, pyroptosis, ferroptosis), yet validated pharmacotherapies remain scarce. Genistein, a soy-derived isoflavone phytoestrogen, has demonstrated multi-organ protection in preclinical IRI models through coordinated regulation of the Nrf2/HO-1 antioxidant axis, SIRT1/p53 deacetylation-dependent anti-apoptotic signaling, and NF-kappaB/JAK2-STAT3/alpha7nAChR/NLRP3 inflammasome cascades, but systematic mechanistic integration is lacking. A narrative review with systematic literature identification was conducted using PubMed/MEDLINE, Web of Science, and Scopus (2010-2024). Studies on genistein or its structurally defined derivatives in established IRI models with mechanistic endpoints were included; soy extracts, biochanin A, and non-IRI studies were excluded. Genistein engages multiple cytoprotective pathways with organ-dependent evidence strength. Causal validation (Level A: genetic deletion, siRNA, or pharmacological inhibitor with rescue) has been achieved for Nrf2/HO-1 in cerebral IRI and for SIRT1/p53, ADORA2A-cAMP-PK, and PI3K/Akt in renal IRI, whereas hepatic and intestinal evidence remains correlative (Level C). SIRT1-mediated deacetylation concurrently suppresses both p53-dependent apoptosis (Bax/PUMA) and NF-kappaB p65 subunit transcriptional activity at Lys310, integrating anti-apoptotic and anti-inflammatory effects. Genistein inhibits NLRP3 inflammasome activation at the priming level (NF-kappaB-dependent NLRP3/pro-IL-1beta transcription) and assembly level (ROS/ASC/caspase-1), linking oxidative stress sensing to gasdermin D-mediated pyroptosis. Emerging evidence (2023-2025) suggests genistein may attenuate ferroptosis via iron chelation and Nrf2-driven GPX4 preservation. Translational gaps include concentration disconnect between
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