Nicotinamide mononucleotide promotes female germline stem cell proliferation by activating the H4K16ac-Hmgb1-Fyn-PLD signaling pathway through epigenetic remodeling.
Level 5 - mechanism / opinion, no new human data
In vitro bench/molecular mechanistic study without human or in vivo data
PubMed 40247362 · doi:10.1186/s13578-025-01387-w
What was done
Researchers investigated the cellular and epigenetic mechanisms by which nicotinamide mononucleotide (NMN) affects female germline stem cell (FGSC) viability and proliferation in vitro. They analyzed molecular pathways using quantitative acetylation proteomics, chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing (RNA-seq), ChIP-qPCR, and high-throughput chromosome conformation capture (Hi-C). Functional validation was performed using Hmgb1 knockdown, Fyn overexpression, dual-luciferase reporter assays, and pharmacological phospholipase D (PLD) inhibition with 5-fluoro-2-indolyldechlorohaloamide.
What was found
The abstract reports directional pathway mechanisms but provides no numerical values, effect sizes, or statistics: - NMN enhanced FGSC viability, proliferation, and histone H4 lysine 16 acetylation (H4K16ac). - Hmgb1 was identified as a downstream target of H4K16ac; Hmgb1 knockdown reduced proliferation, disrupted cell cycle, induced apoptosis, decreased chromatin accessibility, altered 3D chromatin organization (A/B compartment switching, increased TADs, decreased chromatin loops), and lost the chromatin loop at the Fyn promoter. - Fyn overexpression rescued the proliferation deficits of Hmgb1 knockdown via the PLD pathway by selectively increasing PLD1 phosphorylation at Thr147 (not Ser561). - Chemical inhibition of PLD abolished the rescue effect of Fyn overexpression.
Why it matters
The study outlines an epigenetic and 3D-chromatin architecture pathway (H4K16ac-Hmgb1-Fyn-PLD) through which NMN supports germline stem cell self-renewal and proliferation in vitro, providing fundamental mechanistic biology for reproductive stem cell research.
Limits
This is strictly an in vitro bench mechanism study without in vivo animal or human verification. The abstract omits all sample sizes (n), statistical significance levels, and quantitative effect sizes. Applicability to intact ovarian physiology or clinical fertility remains unproven.
Cited by
- supports Nicotinamide mononucleotide (NMN) alters the epigenome and modulates the immune system.