Life sciences · 2026
Salvianolic acid A inhibits tumor cell proliferation and induces chromosomal abnormalities by blocking the citrullinating enzyme PADs.
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Chen Jun, Wang Tiantian, Gao Bei, Ke Xisong, Zhou Xianglian, Qu Yi
Аннотация
AIMS: Citrullination, a post-translational modification catalyzed by peptidylarginine deiminases (PADs), is closely linked to cancer progression. Despite PADs' clinical importance, effective inhibitors are urgently needed. We aimed to identify a novel PAD inhibitor, salvianolic acid A (SAA), and to characterize the mechanism by which SAA inhibits PAD activity and exerts anti-tumor effects.
MATERIALS AND METHODS: Citrullination of histone H3 (CitH3), drug affinity responsive target stability (DARTS) assays, in vitro enzymatic activity, and molecular docking were used to investigate SAA's direct interaction with PAD family members. PAD oligomerization was evaluated by disuccinimidyl suberate (DSS) cross-linking, native PAGE, and proximity ligation assay (PLA). PAD-histone H3 interaction was assessed by co-immunoprecipitation and PLA. Cellular effects were evaluated in colorectal cancer cell lines and mouse intestinal organoids using CCK-8, Transwell, EdU, and karyotype analyses.
KEY FINDINGS: SAA was identified as a reversible pan-PAD inhibitor that binds directly to PAD1, PAD2, PAD3, and PAD4. Unlike traditional covalent inhibitors, SAA promotes PAD oligomerization and enhances PAD-histone H3 interaction while inhibiting histone H3 citrullination. SAA significantly inhibited cancer cell proliferation, migration, and organoid growth, and induced numerical chromosomal abnormalities in a PAD2/4-dependent manner.
SIGNIFICANCE: These findings establish PADs as functional targets of SAA and reveal a novel mechanism for PAD inhibition, positioning SAA as a promising chemical probe for treating citrullination-related diseases.
MATERIALS AND METHODS: Citrullination of histone H3 (CitH3), drug affinity responsive target stability (DARTS) assays, in vitro enzymatic activity, and molecular docking were used to investigate SAA's direct interaction with PAD family members. PAD oligomerization was evaluated by disuccinimidyl suberate (DSS) cross-linking, native PAGE, and proximity ligation assay (PLA). PAD-histone H3 interaction was assessed by co-immunoprecipitation and PLA. Cellular effects were evaluated in colorectal cancer cell lines and mouse intestinal organoids using CCK-8, Transwell, EdU, and karyotype analyses.
KEY FINDINGS: SAA was identified as a reversible pan-PAD inhibitor that binds directly to PAD1, PAD2, PAD3, and PAD4. Unlike traditional covalent inhibitors, SAA promotes PAD oligomerization and enhances PAD-histone H3 interaction while inhibiting histone H3 citrullination. SAA significantly inhibited cancer cell proliferation, migration, and organoid growth, and induced numerical chromosomal abnormalities in a PAD2/4-dependent manner.
SIGNIFICANCE: These findings establish PADs as functional targets of SAA and reveal a novel mechanism for PAD inhibition, positioning SAA as a promising chemical probe for treating citrullination-related diseases.