Short-chain fatty acids (SCFAs) are microbial metabolites produced by the gut microbiome through the fermentation of dietary fibers and non-digestible carbohydrates. SCFAs have received considerable interest as potential regulators of various cancers, including colorectal cancer and breast cancer. However, their roles and underlying mechanisms in ovarian cancer remain elusive. This study aimed to investigate and compare the anti-cancer effects of sodium butyrate (NaB) and sodium propionate (NaP) in two distinct ovarian cancer cell lines, SKOV-3 and PA-1.

Both NaB and NaP significantly reduced proliferation and colony formation, and impaired spheroid formation of SKOV-3 and PA-1 cells in a dose- and time-dependent manner. Notably, NaB exhibited greater anti-cancer potency than NaP, as evidenced by its lower IC₅₀ values—being 4.8-fold and 3.2-fold lower at 72 h and 96 h, respectively, in SKOV-3 cells, and 4.4-fold and 1.7-fold lower at 72 h and 96 h, respectively, in PA-1 cells. Additionally, treatment with NaB for 24 h and with NaP for 24–48 h induced cell cycle arrest at the G2/M phase in both cell lines, accompanied by an upregulation of p21 and a decrease in the expression of cyclins A2, B1, and B2. Moreover, 48 h post-treatment, both compounds induced apoptosis, with NaB demonstrating more pronounced effects. NaB increased the percentage of late apoptotic cells to 21.85% at 10 mM in SKOV-3 cells and to 69.9% at 5 mM in PA-1 cells, while 15 mM NaP resulted in 4.3% and 16.8% late apoptotic cells in SKOV-3 and PA-1, respectively. This was accompanied by modulation of apoptosis-regulatory proteins, including PARP-1 cleavage and an increased BAX/BCL2 ratio in the treated cells, suggesting the involvement of the intrinsic apoptotic pathway.

Our study demonstrated that NaB and NaP inhibited the growth and survival of two different ovarian cancer subtypes through cell cycle arrest and apoptosis. While NaB exhibited greater potency, our findings highlight the promising therapeutic potential of both compounds in ovarian cancer and lay the groundwork for further mechanistic and clinical studies.