{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T15:58:21Z","timestamp":1783180701593,"version":"3.54.6"},"reference-count":38,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Polycystic ovarian syndrome (PCOS), a common endocrine disorder in reproductive-aged women, is linked to circadian rhythm disruption, but the molecular mechanisms remain unclear. Dysregulation of the lncRNA TCONS_00265853-miR-421-5p-CLOCK axis may play an important role. Ziyin Buyang Formula (ZYBYF), a Traditional Chinese Medicine (TCM) targeting kidney Yin-Yang balance, shows therapeutic potential, though its mechanism is unclear. This study explores ZYBYF\u2019s role in modulating this axis to improve circadian-disrupted PCOS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Network pharmacology identified ZYBYF\u2019s bioactive components and targets, integrated with PCOS-associated genes and circadian disruption-related differentially expressed genes (DEGs) from ovarian tissues. A continuous light-induced PCOS rat model (10-week 24-h light exposure) was employed to validate ZYBYF\u2019s effects. Interventions included ZYBYF treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Bioinformatics identified 25 intersection targets, with MAPK signaling as the central pathway. <jats:italic>In vivo<\/jats:italic>, circadian disruption downregulated lncRNA TCONS_00265853 and <jats:italic>CLOCK<\/jats:italic>, elevated miR-421-5p, and hyperactivated MAPK (p-p38, p-ERK1\/2, p-JNK), exacerbating ovarian apoptosis (\u2191BAX, \u2193Bcl-2, p &amp;lt; 0.001). ZYBYF restored circadian axis components (\u2191TCONS_00265853, <jats:italic>CLOCK<\/jats:italic>; \u2193miR-421-5p), suppressed MAPK activation, and normalized ovarian morphology and hormonal profiles (\u2193LH, T, ACTH; \u2191E2, FSH, p &amp;lt; 0.001). PRKCA expression, a MAPK regulator, was rescued by ZYBYF, counteracting dysregulation of <jats:italic>IL1B<\/jats:italic>, <jats:italic>VEGFA<\/jats:italic>, and <jats:italic>TGFB1<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Circadian disruption exacerbates PCOS via the TCONS_00265853-miR-421-5p-<jats:italic>CLOCK<\/jats:italic> axis, driving MAPK hyperactivation and ovarian apoptosis. ZYBYF reverses these effects, restoring hormonal balance and follicular dynamics. This study provides mechanistic validation of ZYBYF\u2019s efficacy, positioning it as a promising therapeutic strategy for circadian-disrupted PCOS. These findings suggest that ZYBYF may modulate circadian rhythm\u2013related pathways in PCOS via the lncRNA\u2013miRNA\u2013CLOCK axis, warranting further mechanistic validation.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1658812","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T04:18:38Z","timestamp":1759897118000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulation of the lncRNA TCONS_00265853-miR-421-5p-CLOCK axis by Ziyin Buyang Formula in polycystic ovarian syndrome with circadian rhythm disruption: an integrated bioinformatics and experimental approach"],"prefix":"10.3389","volume":"16","author":[{"given":"Haixia","family":"Huang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Jia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yahong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.ejogrb.2004.07.024","article-title":"Vascular endothelial growth factor and insulin-like growth factor-1 in polycystic ovary syndrome and their relation to ovarian blood flow","volume":"118","author":"Abd El Aal","year":"2005","journal-title":"Eur. 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