PCa arises from a complex interplay of genetic, metabolic, and hormonal perturbations. In the cross-phenotype analysis of PCa, we found multiple risk-associated traits, including proteomic biomarkers (PSA), metabolic dysregulation (central obesity, HDL dysfunction, hypertension), and androgen signaling (balding), collectively underscoring PCa’s multifactorial etiology.
PSA, a protein secreted by both normal and malignant prostate epithelial cells, has long been a cornerstone in the early detection and monitoring of PCa. However, the specificity and sensitivity of PSA as a diagnostic tool have been questioned due to its elevation in benign conditions such as prostatitis and benign prostatic hyperplasia (BPH), leading to unnecessary biopsies and substantial overdiagnosis (Gudmundsson et al., 2018; Ilic et al., 2018; Kalavacherla et al., 2023). Therefore, complementary biomarkers are urgently needed to improve diagnostic accuracy. Our PW-MR study revealed that genetically plasma MSMB levels were causally associated with PCa risk. Importantly, this aligns with the clinical utility of urinary MSMB: a quadriplex urine panel (MSMB, TRPM8, AMACR, PCA3) improved diagnostic accuracy in PCa patients compared to PSA alone (Jamaspishvili et al., 2011). While plasma MSMB reflects systemic risk, urinary MSMB captures localized prostate pathology, together offering complementary insights into PCa biology. In conclusion, systematic integration of proteomic biomarkers identified through causal inference frameworks with PSA-based screening offers a path to resolve the persistent challenges of PCa diagnostic accuracy.
Emerging evidence implicates metabolic syndrome (MetS), which encompasses a cluster of conditions, including central obesity, dyslipidemia, and hypertension, may be a risk factor of PCa and may also worsen outcomes (Hernández-Pérez et al., 2022; Lifshitz et al., 2021). The significant association between BMI-adjusted WHR and advanced PCa risk suggested that central obesity may play a critical role in the development of PCa (Genkinger et al., 2020; Perez-Cornago et al., 2022). Visceral adiposity may increase risk of advanced forms of PCa through changes in cytokines and growth factors, hormone regulation, and metabolism (Doyle et al., 2012; Himbert et al., 2017). These metabolic perturbations extend beyond obesity itself, intersecting with broader lipid and inflammatory pathways that further modulate PCa risk. For instance, HDL cholesterol, while classically recognized for its cardioprotective roles in reverse cholesterol transport and antioxidant and anti-inflammatory activities (Rohatgi et al., 2021), may also antagonize prostate carcinogenesis. Epidemiological and preclinical studies found that HDL may suppress prostate carcinogenesis by reducing oxidative stress and the levels of pro-inflammatory molecules in cancer cells and TME (Ossoli et al., 2022; Ruscica et al., 2018). However, in obesity, HDL’s antioxidant and anti-inflammatory capacity is impaired due to altered composition and reduced functionality (Bacchetti et al., 2024), while adipose-derived ROS and cytokines further amplify oxidative damage (Balan et al., 2024). The loss of HDL protection and obesity-driven oxidative stress provides a physiological mechanistic basis for obesity-associated PCa aggressivity. This metabolic-inflammatory axis extends to hypertension, which is another MetS hallmark. Although results from previous studies of the association between hypertension and PCa development remain inconsistent (Christakoudi et al., 2020; Liang et al., 2016; Seretis et al., 2019), an MR analysis suggested that elevated systolic blood pressure might increase PCa risk through systemic inflammation (Stikbakke et al., 2022), a mechanism similar to that of central obesity and HDL dysfunction. Chronic inflammation contributes to a pro-tumorigenic environment by promoting cellular proliferation, DNA damage, and resistance to apoptosis (Mantovani et al., 2008). Thus, MetS components likely converge on overlapping pathways to accelerate PCa progression, though the precise relationship between systolic blood pressure and PCa remains unclear. More research is needed to elucidate the exact biological pathways involved and to determine whether managing clinical features of MetS could serve as a preventive strategy for PCa.
The link between androgenic alopecia (AGA) and PCa risk further implicates androgen metabolism as a central driver, as both conditions are influenced by dihydrotestosterone (DHT) levels. In AGA, DHT binds to androgen receptors (AR) in the dermal papilla cells, causing follicular miniaturization and hair loss (Urysiak-Czubatka et al., 2014). Similarly, DHT-driven AR activation in prostate epithelial cells promotes proliferation and inhibits apoptosis, fostering tumorigenesis (Tong et al., 2022). However, the link between AGA and PCa may not be solely hormone-dependent. Genetic pleiotropy, where variants in loci such as AR or SRD5A2 influence both balding and prostate carcinogenesis, could partially explain this association (Hayes et al., 2005; Hayes et al., 2007). Further studies are needed to confirm the causality.
Overall, our cross-phenotype analysis provided a comprehensive view of the diverse factors associated with PCa and enhanced our understanding of the disease’s multifaceted nature. Future research should focus on elucidating the underlying mechanisms of these associations and exploring their potential for integration into clinical practice.