Abstract
Background:
Primary liver cancer (PLC) poses a significant global health threat, with sex hormones implicated in its pathogenesis. Testosterone and estradiol's influence on PLC risk remains debated. Mendelian randomization (MR) offers a robust method to assess causal relationships.
Methods:
We conducted MR analyses using genome-wide association study (GWAS) data to investigate the causal impact of testosterone and estradiol on PLC risk. Tumor necrosis factor receptor superfamily member 9(TNFRS9) and urokinase-type plasminogen activator(uPA) were explored as potential mediators.
Results:
Our MR analysis revealed a protective effect of testosterone and estradiol against PLC. Testosterone was negatively associated with PLC risk (OR = 0.9987, P = 0.0316), with TNFRS9 mediating 9.1% of this effect. Estradiol exhibited a negative correlation with PLC risk (OR = 0.9985, P = 0.0125), with uPA mediating 8% of this effect.
Conclusions:
Contrary to traditional beliefs, both testosterone and estradiol demonstrate protective effects against PLC. TNFRS9 and uPA pathways mediate a significant portion of these effects, providing novel insights into the sex hormone-PLC relationship and potential therapeutic targets. Further research should validate these findings across diverse populations.