SIRT3 and Uterine Fibroids — A Mitochondrial Guardian in Uterine Tissue
Uterine fibroids (leiomyomas) affect an estimated 70–80% of women by age 50 and are
among the leading indications for hysterectomy worldwide. The mechanisms underlying
fibroid development involve a combination of estrogen sensitivity, dysregulated
proliferation, and — increasingly recognised —
oxidative stress and mitochondrial dysfunction11 oxidative stress and mitochondrial dysfunction
Reactive oxygen species (ROS) promote
smooth muscle cell proliferation and extracellular matrix deposition, both hallmarks of
fibroid growth. SIRT3 sits at the centre
of the mitochondrial antioxidant network, and variants that may alter its expression or
activity could modestly shift the threshold for fibroid formation in susceptible women.
SIRT3 (Sirtuin 3) is the principal
NAD⁺-dependent protein deacetylase22 NAD⁺-dependent protein deacetylase
SIRT3 removes acetyl groups from lysine residues
on mitochondrial proteins, activating enzymes involved in energy metabolism and
antioxidant defence inside mitochondria.
Its major substrates include MnSOD2 (the primary mitochondrial superoxide scavenger),
IDH2 (which regenerates the NADPH needed to recycle glutathione), and complexes of the
electron transport chain. When SIRT3 activity is adequate, mitochondrial ROS remain
controlled; when SIRT3 is reduced, ROS accumulate and can drive cell proliferation and
fibrosis — two defining features of fibroid growth.
The Mechanism
rs547025 is located in intron 6 of SIRT3 on chromosome 11p15.5, within a gene region that contains a characterised enhancer variable-number tandem repeat (VNTR) in intron 5. While rs547025 itself sits approximately 128 bp into the intron adjacent to exon 3 in some transcripts (HGVS: c.280+128A>G on the coding strand), the broader SIRT3 locus contains regulatory elements capable of allele-specific variation in transcriptional efficiency.
The link to fibroid tissue is directly supported by protein-expression data: normal
myometrial tissue expresses substantially higher SIRT3 protein than matched uterine
fibroid tissue in the same women. When SIRT3 is activated pharmacologically in human
leiomyoma (HuLM) cells, proliferation and collagen deposition are selectively suppressed,
while normal uterine smooth muscle (UTSM) cells are unaffected — indicating that
lower SIRT3 expression is a feature of, and may contribute to, the fibroid phenotype33 lower SIRT3 expression is a feature of, and may contribute to, the fibroid phenotype
Conference abstract, Fertility & Sterility 2020: honokiol (a SIRT3 activator) inhibits
HuLM leiomyoma cell growth selectively while UTSM cells resist treatment at all tested
doses.
A parallel line of evidence comes from the myometrium during parturition: SIRT3 expression falls sharply in term laboring myometrium relative to non-laboring myometrium, and SIRT3 knockdown in primary myometrial cells amplifies NF-κB signalling, driving production of pro-inflammatory cytokines (IL-6, CXCL8), prostaglandins (via PTGS2), and matrix metalloproteinases.
The Evidence
The primary evidence linking rs547025 specifically to fibroid risk comes from a
case-control study of 737 Central Russian women with ultrasound-confirmed uterine fibroids
and 451 controls44 case-control study of 737 Central Russian women with ultrasound-confirmed uterine fibroids
and 451 controls
Ponomareva, Kobzeva, Bushueva et al. Front Biosci (Schol Ed), 2024.
PMID 39736018.
Probe-based PCR was used to genotype seven GWAS-significant SNPs. The C allele of
rs547025 was associated with a statistically significant reduction in fibroid risk in the
overall cohort (OR = 0.61, 95% CI 0.43–0.87, p = 0.005), placing it among the
strongest single-locus protective associations in the panel. Subgroup analyses revealed
that protection was most pronounced in women with normal fruit and vegetable intake
(OR = 0.39, 95% CI 0.21–0.75, p = 0.002), no prior spontaneous abortions
(OR = 0.48, 95% CI 0.33–0.70, p = 0.0001), and no prior pelvic inflammatory disease
(OR = 0.55, 95% CI 0.38–0.80, p = 0.002).
The broader SIRT3 locus at 11p15.5 has independently appeared in uterine fibroid GWAS datasets, and rs73392700 — an intronic SIRT3 variant identified in a multi-ancestry GWAS — showed an OR of 0.77 (95% CI 0.74–0.79, p = 1.09 × 10⁻⁵⁰) in East Asian and Central/South Asian ancestry analyses, confirming that protective variation in the SIRT3 locus for fibroids is not restricted to one population.
The evidence at the specific rs547025 locus is based on a single case-control study from a Central Russian population and has not yet been independently replicated; the evidence level is therefore rated moderate. The biological rationale is plausible and supported by functional data from fibroid tissue expression studies, but replication in independent cohorts is needed before clinical utility can be established.
Practical Implications
Carrying two copies of the common T allele (TT) removes the modest protection associated with the C allele. This does not meaningfully change population-level fibroid risk on its own — the absolute difference conferred by a single variant of this effect size is small — but it may be relevant when considered alongside other fibroid risk factors: African ancestry, nulliparity, obesity, early menarche, vitamin D deficiency, and family history.
SIRT3's primary substrate pathway (NAD⁺ → SIRT3 → MnSOD2/IDH2 → glutathione
regeneration) is nutritionally modifiable: SIRT3 requires NAD⁺ as a cofactor, and
NAD⁺ declines with age and metabolic stress55 NAD⁺ declines with age and metabolic stress
The SIRT3/NAD⁺ axis is a recognised
mechanism for age-related mitochondrial dysfunction and a target of active supplementation
research | Weir et al. 2013.
Interactions
rs7986407 (FOXO1, 13q14.11): FOXO1 is a decidualization marker downstream of estrogen receptor signalling, and the rs7986407 locus reached genome-wide significance for fibroid risk (OR ≈ 1.09, p = 1.2 × 10⁻¹¹) in UK Biobank GWAS. Both rs547025 (SIRT3) and rs7986407 (FOXO1) were included in the Ponomareva 2024 panel. SIRT3 and FOXO1 operate on converging pathways: SIRT3 deacetylates and activates FOXO3a (a related FOXO family member), which in turn upregulates MnSOD2. FOXO1 similarly controls oxidative stress gene expression in uterine stroma.