{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nManganese superoxide dismutase (SOD2) is a pivotal mitochondrial enzyme that converts the superoxide radical to hydrogen peroxide, thereby maintaining redox homeostasis and protecting cells from oxidative stress–induced damage and apoptosis. Its expression is tightly regulated at multiple levels. In quiescent cells, activation of transcription factors such as FOXO3a supports SOD2 gene induction, conferring resistance to nutrient‐deprivation–induced apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Post‐translational mechanisms also critically modulate its activity; for example, acetylation at a conserved lysine residue dampens its enzymatic function while mitochondrial deacetylases like SIRT3, activated in response to reactive oxygen species (ROS), restore its activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, nuclear SIRT1, by relocating into the nucleus under conditions such as heart failure, further induces SOD2 to promote cardiomyocyte survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Additional redox‐dependent signaling cascades—such as those mediated by protein kinase D and NF‑κB—and epigenetic modifications including altered histone methylation, as well as transcriptional control via Sp1 and AP‑2, also contribute to fine‐tuning SOD2 levels."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in SOD2 expression and activity have broad implications in disease pathogenesis, particularly in cancer and other redox‐driven disorders. Genetic studies have associated polymorphisms in its mitochondrial targeting sequence with modified risks for several malignancies—including breast, prostate, ovarian, and lung cancers—and meta‐analyses further suggest that variant SOD2 alleles can modulate susceptibility in conditions as diverse as tardive dyskinesia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": " Functionally, SOD2 overexpression has been implicated in redox‐dependent processes that promote tumor cell survival, metabolic reprogramming, and even angiogenesis through mechanisms such as PTEN oxidation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": " Elevated SOD2 levels also feature in inflammatory and degenerative diseases—for instance, increased expression is noted in active multiple sclerosis lesions, while reduced SOD2 characterizes osteoarthritic chondrocytes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " In addition, the detection of autoantibodies against SOD2 in membranous nephropathy emphasizes its immunological relevance"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": ", and further analyses have uncovered its participation in colorectal cancer risk through interactions with selenium‐related antioxidant pathways."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "28"}]}, {"type": "t", "text": " Finally, upregulation of SOD2 in transformed cells has been shown to sustain hydrogen peroxide production that activates AMP‑activated kinase and promotes the metabolic shift to glycolysis, a key feature of aggressive tumor phenotypes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Geert J P L Kops, Tobias B Dansen, Paulien E Polderman, et al. 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