Tier 3 — preclinical

Beneficial Effects of Fisetin, a Senotherapeutic Compound, in Women's Reproductive Health and Diseases: Evidence from In Vitro to Clinical Studies

Samya El Sayed, D'leela Saiyed, Valeria I. Macri, Awurakua Asamoah-Mensah, James H. Segars, Md Soriful Islam
Nutrients 2026 Volume 18, issue 3, article 393

Bibliography

PubMed
PMID 41683217
PubMed Central
PMC12899922
DOI
10.3390/nu18030393
Funding
This research was supported, in part, by NIH grant R01HD111243, the Howard W. and Georgeanna Seegar Jones Endowment, and the Ernest and Barbara Bernstein Endowment.
Competing interests
S.E.S. has nothing to disclose. D.S. has nothing to disclose. V.I.M. has nothing to disclose. A.A.-M. has nothing to disclose. J.H.S. is, or was, a PI in research sponsored by Bayer, Organon LLC, Myovant, May Health, Heranova Life Sciences, and Aspira Labs, and has served as a scientific advisor/consultant for Cadenza Bio and the Blueprint Medicines Corporation. M.S.I. has nothing to disclose.

Study snapshot

DesignNarrative literature review
ModelIn vitro, in vivo, and clinical studies of fisetin in ovarian aging, fertility, menopause, endometriosis, uterine fibroids, PCOS, and gynecological cancers
SampleNot applicable — narrative review; no formal PRISMA count
InterventionFisetin across all reviewed doses, formulations, and routes (dietary, oral, intraperitoneal, in vitro exposure, nanoformulations)
DurationLiterature search conducted via PubMed, Google Scholar, and ClinicalTrials.gov through December 2025
EndpointsAntioxidant, anti-inflammatory, and senotherapeutic mechanisms of fisetin; Effects on ovarian aging, oocyte quality, and fertility · Effects in menopause and bone preservation; Effects in endometriosis, uterine fibroids, and PCOS; Antitumor effects in ovarian and cervical cancer · Safety and feasibility from registered clinical trials

What the study showed, in plain terms

Fisetin is a plant flavonoid found in strawberries, apples, persimmons, and onions. It has three properties that matter for women's reproductive health: it neutralises free radicals (antioxidant), calms overactive inflammation (anti-inflammatory), and clears senescent cells — worn-out cells that stop dividing but stay behind and release harmful signals into surrounding tissue (senolytic).

This review pulls together the evidence for fisetin across seven areas: ovarian aging, fertility, menopause, endometriosis, uterine fibroids, polycystic ovary syndrome (PCOS), ovarian cancer, and cervical cancer. In every one of these areas, laboratory and animal studies suggest fisetin may help — reducing senescent cell burden in aging ovaries, protecting oocytes from oxidative damage, easing inflammation and fibrosis in endometriosis and fibroids, restoring hormonal balance in PCOS, and triggering cancer cell death in gynecological tumours. The authors also catalogue every registered clinical trial of fisetin in humans, showing an emerging safety profile from work in frailty, cancer survivorship, and osteoarthritis.

The important caveat: no clinical trial has yet tested fisetin in any gynecological or reproductive condition. The two clinical trials in women (both in breast cancer survivors) are ongoing. Everything else is preclinical. Fisetin also has poor oral bioavailability — most of a dose is broken down before it reaches the tissues where it might act — which is why newer formulations (liposomes, nanoemulsions, hydrogel systems) are being developed. The review positions fisetin as promising but not yet proven for women's reproductive health.

Key findings

  • Ovarian aging: Fisetin (50 mg/kg/day in laying hens; 1–20 μM in mouse oocytes) reduced oxidative stress, improved mitochondrial ATP production, and downregulated senescence markers p53, p21, and p16 via Nrf2/HO-1 and Wnt/β-catenin signalling.
  • Fertility: Fisetin modulated the Sirt1 pathway to delay postovulatory oocyte aging in mice, and 50 μM fisetin in cryopreservation medium improved sperm DNA preservation and motility in a human semen study.
  • Menopause: 50 μM fisetin supported bone preservation in chondrocyte and pre-osteoblast cell lines, suggesting a role against postmenopausal bone loss via its senolytic action.
  • Endometriosis: 40 mg/kg oral fisetin in a Sprague Dawley rat model reduced lesion size, mast cell activation, IL-1β, TNF-α, collagen deposition, α-SMA, and TGF-β; it also enhanced decidualization in primary human endometrial stromal cells at 25–50 μM.
  • Uterine fibroids: In the only fibroid-specific study to date, fisetin killed leiomyoma cells preferentially over normal myometrial cells starting at 20 μM, activating intrinsic apoptosis, extrinsic apoptosis, p53, MAPK, and autophagy pathways simultaneously.
  • PCOS: Across three rat models (letrozole and mifepristone-induced), 1.25–40 mg/kg fisetin lowered testosterone, LH, fasting glucose, and HOMA-IR; raised AMH, progesterone, and antioxidant enzymes (GSH, SOD, CAT, GPX); and restored normal follicular development. Efficacy comparable to metformin in one study, though not head-to-head equivalent.
  • Ovarian cancer: Fisetin (25–100 μM) reduced viability in A2780, OVCAR-3, and SKOV3 lines via apoptosis and necroptosis (ZBP1, RIP3, MLKL activation), restored platinum sensitivity in mesenchymal-stem-cell-induced resistant models, and — as polymeric micelles — achieved 70.7% tumour growth inhibition in SKOV3 xenografts vs 53.6% for free fisetin.
  • Cervical cancer: Fisetin reduced HeLa cell viability with IC50 of 36–52 μM, activated both intrinsic and extrinsic apoptosis, suppressed MAPK and PI3K/AKT/mTOR, inhibited uPA-mediated invasion in SiHa and CaSki cells, and synergised with sorafenib in HeLa xenografts.
  • Clinical trials: Two phase 2 trials in breast cancer survivors are ongoing (NCT06113016, NCT05595499). No trial has yet enrolled in any gynecological or reproductive condition. Safety data from >20 completed or ongoing trials in other conditions support tolerability.
  • Bioavailability: Oral bioavailability of free fisetin is 7.8–31.7%; formulations (liposomes, nanoemulsions, nanocochleates, SNEDDS, fenugreek–galactomannan hydrogel FF-20) increase AUC by 24- to 141-fold in various models.

What this study can and cannot tell us

  • No gynecological clinical trials. Every finding in reproductive or gynecological conditions is preclinical — cell culture or animal model. The two registered clinical trials in women are both in breast cancer survivors, not in any of the conditions this review covers.
  • Concentration mismatch. In vitro concentrations reviewed range from 5 to 300 μM. Plasma fisetin after oral dosing in humans reaches low-to-mid micromolar range at best, and only with advanced formulations. Whether the cellular effects reported here are achievable in living reproductive tissue at safe doses is unknown.
  • Narrative review, not systematic. The authors state explicitly that this review does not follow a systematic framework, includes no formal quality assessment or risk-of-bias evaluation, and searched only English-language literature.
  • Head-to-head comparisons missing. Where fisetin is described as "comparable to metformin" in PCOS or as a chemotherapy adjunct in ovarian cancer, dose equivalence and direct mechanistic comparisons with standard-of-care agents were not established in the underlying studies.
  • Long-term safety unstudied in reproductive contexts. Interactions with hormonal contraceptives, HRT, chemotherapy, and anticoagulants have not been evaluated in any of the reviewed populations.
  • Contradictory findings noted. In one reproductive-age mouse study (Garcia et al.), 100 mg/kg fisetin reduced senescence markers but did not improve ovarian reserve or fertility — a reminder that senolytic biomarker changes do not always translate to functional benefit.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology