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We previously demonstrated that ovulatory follicular fluid (FF) released reactive oxygen species (ROS), which activate activation\u2010induced cytidine deaminase (AID) and promote\n                    <jats:italic>TP53<\/jats:italic>\n                    mutagenesis in FTE. Here, we demonstrate that hemoglobin (Hb) originating from retrograde menstruation acts as an extracellular ROS scavenger, attenuating AID\u2010mediated\n                    <jats:italic>TP53<\/jats:italic>\n                    deamination in fallopian tube fimbriae, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Peritoneal fluid from tubal\u2010ligated women exhibited significantly lower Hb, higher ROS, and elevated hypoxanthine phosphoribosyl transferase (\n                    <jats:italic>HPRT<\/jats:italic>\n                    ) mutagenic activity compared to nonligated controls (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.004). Histopathological analysis of 206 fallopian tubes from 119 women undergoing opportunistic salpingectomy further revealed a significantly higher frequency of p53 signatures in ligated tubes (0.22\u2009\u00b1\u20090.64 lesions per fimbria) than in nonligated tubes (0.07\u2009\u00b1\u20090.31 lesions per fimbria) (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.017). Multivariate analysis identified tubal ligation as the sole reproductive factor independently associated with p53 signatures [odds ratio (OR)\u2009=\u20093.32; 95% CI: 1.15\u20139.57]. Our findings indicate that retrograde menstrual Hb mitigates ovulation\u2010associated ROS stress, thereby reducing AID\u2010mediated\n                    <jats:italic>TP53<\/jats:italic>\n                    mutagenesis in the FTE. This study uncovers a physiological, protective role for menstruation against ovulatory oxidative damage and its mutagenic consequences, while demonstrating that tubal ligation disrupts this endogenous antioxidant mechanism, resulting in an increased burden of p53 signature lesions. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70064","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:43:44Z","timestamp":1777452224000},"page":"337-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Tubal ligation exacerbates ovulation\u2010driven\n                    <scp>\n                      <i>TP53<\/i>\n                    <\/scp>\n                    mutagenesis and p53 signatures by depleting protective menstrual hemoglobin"],"prefix":"10.1002","volume":"269","author":[{"given":"Kanchana","family":"Subramani","sequence":"first","affiliation":[{"name":"Center for Prevention and Therapy of Gynecological Cancers, Department of Research Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  Hualien Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng\u2010Chuan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Clinical Pathology and Anatomic Pathology Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  Chiayi Taiwan"},{"name":"School of Medicine, Tzu Chi University  Hualien Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen\u2010Hung","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Research Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation  Hualien 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