Aim To study the effect of momordicin 28 (MD28) on the expression of apolipoprotein(a) in HepG2 cells and explore its mechanism. Methods The cell viability of HepG2 cells treated with MD28 was determined by MTT assay. MD28 was purified by centrifugation, ultrafiltration, dialysis, cation exchange chromatography and reversed-phase high performance liquid chromatography. The mRNA and protein expression levels of apolipoprotein(a), farnesyl ester X receptor (FXR) and hepatocyte nuclear factor 4α (HNF4α) were detected by qRT-PCR and Western blot respectively, qRT-PCR was used to detect the expression level of hsa-miR-23b-3p, and small interfering RNA transfection was used to silence FXR. Results Compared with the control group, the cell viability of HepG2 cells treated with MD28 at 0.1,0.2,0.4,0.8 and 1.6 g/L had no significant difference. Compared with the control group, MD28 inhibited apolipoprotein(a) expression in a dose and time dependent manner, the best inhibitory effect was 1.6 g/L MD28 on 48 h. FXR and hsa-miR-23b-3p expression levels were up-regulated by MD28 while HNF4α was down-regulated in HepG2 cells, and silencing FXR reversed above-mentioned effect of MD28, silencing hsa-miR-23b-3p could also reverse the down-regulation effect of MD28 on HNF4α, but had no effect on FXR expression. Conclusion MD28 inhibits the expression of Apo(a) in HepG2 cells through the FXR/miR-23b-3p/HNF4α pathway, and is expected to be a candidate for the clinical reduction of lipoprotein(a).