Sex-Specific Associations of Total Bilirubin, ALBI, and PALBI with Lung Cancer Risk: Interactions with Smoking and Alcohol

<b>Background:</b> Bilirubin is a potent endogenous antioxidant that plays a key role in regulating oxidative stress and inflammation, both closely linked to lung carcinogenesis. This study reinterprets the ALBI (Albumin-Bilirubin) and PALBI (Platelet-Albumin-Bilirubin) indices as composite markers of antioxidant and inflammatory status and evaluates their associations with lung cancer risk by sex, including stratified analyses by major lifestyle factors such as smoking and alcohol use. <b>Methods:</b> This study utilized data from the Korean Cancer Prevention Study-II (KCPS-II) cohort, which included 133,630 participants. During a mean follow-up of 13.5 years, 721 incident lung cancer cases were identified. Serum bilirubin and the ALBI and PALBI indices were analyzed by sex, and quartile-based and trend analyses were conducted. Stratified analyses by smoking and alcohol status (never, former, current, ever) and intensity were performed to assess potential effect modification. Cox proportional hazards regression models were used to estimate HRs and 95% CIs. <b>Results</b>: A 1SD increase in total bilirubin and ALBI was inversely associated with lung cancer risk in men (HR: 0.83, 95% CI: 0.75-0.91; HR: 0.86, 95% CI: 0.79-0.94, respectively), whereas PALBI showed a positive association (HR: 1.17, 95% CI: 1.07-1.28). In contrast, in women, total bilirubin and ALBI showed positive associations (HR: 1.19, 95% CI: 1.00-1.40; HR: 1.19, 95% CI: 1.02-1.40, respectively), while PALBI was inversely associated (HR: 0.82, 95% CI: 0.69-0.97). These associations were significant among men who were smokers (former, current, ever) and men who drank alcohol (current, ever), whereas in women, significance was observed only among never drinkers. Stronger interactions were observed in men who were heavy smokers and low-to-moderate drinkers. <b>Conclusions:</b> Bilirubin and the ALBI and PALBI indices exhibit sex-specific and contrasting associations with lung cancer risk, highlighting the need to consider sex-based physiological differences in cancer risk assessment.