Non-melanoma skin cancer (NMSC) includes basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC) 1. cSCCs have a higher risk of local recurrence and distant metastases and exhibit more aggressive clinical behavior than BCCs 1. Recent articles have cited an increased risk of NMSC with the use of diuretics, proposed to be due to the photosensitizing nature of the medication 2. However, further studies have at times been unable to confirm the said effect on keratinocytic carcinoma risk, nor certain drugs' phototoxic effects 3, 4. Given the widespread use of diuretics in the treatment of cardiovascular diseases, any NMSC risk associated with the use of diuretics is worthy of study, given our understanding that the potential attributable morbidity may have far-reaching consequences. We sought to understand the effect of diuretic use on carcinogenesis by approaching the issue in a translational manner, first investigating the potential impact on a population level, and further attempting to confirm said findings at the bench. Our population-based cohort study included patients with cardiovascular disease in the United States who initiated diuretics and those never exposed to diuretics, between January 2003 and November 2025 (Supporting Information available via Mendeley, doi: 10.17632/fkjn7xghhg.1). Patients who initiated diuretics after baseline were censored to avoid immortal time bias. After propensity score matching, a total of 7,519,717 patients receiving diuretics were included, among whom 78,497 (1.044%) developed cSCC over a mean follow-up of 1393.3 days. It was found that exposure to diuretics was associated with a significantly higher risk of subsequent cSCC (hazard ratio HR = 1.303, 95% confidence interval CI = 1.289–1.318). In the subgroup analysis, where propensity score matching was applied separately for each diuretic class, potassium-sparing diuretics were associated with the highest risk of cSCC (HR = 1.433, 95% CI = 1.399–1.468), followed by thiazides (HR = 1.334, 95% CI = 1.315–1.354) and loop diuretics (HR = 1.342, 95% CI = 1.323–1.362). It was verified that patients exposed to two or more cycles of diuretics presented with a significantly higher risk of cSCC (HR = 1.359, 95% CI = 1.342–1.376) (Table 1). To investigate pathophysiologic mechanisms for the clinical findings, in vitro experiments were conducted to assess the effects of diuretics on primary cell lines derived from human cSCC biopsies (Data S1). As is widely known, uncontrolled cell growth is a primary characteristic of cancer that promotes the development and spread of tumors 5. One representative drug from each examined category was selected to test its effects on cSCC cell proliferation: hydrochlorothiazide, a thiazide diuretic; furosemide, a loop diuretic; and spironolactone, a potassium-sparing diuretic. The EdU incorporation assay showed that furosemide and hydrochlorothiazide, even at higher doses, did not affect cell proliferation. On the contrary, a high concentration of spironolactone increased the proliferation of cSCC cell lines, while not having an effect at lower concentrations (Figure 1). This aligns with our finding that potassium-sparing diuretics were associated with the highest risk of cSCC. Taken together, the epidemiologically observed effects of loop diuretics and thiazide diuretics may arise from systemic and environmental mechanisms, influencing tumor progression rather than having direct cellular effects. In contrast, spironolactone might directly influence cancer cell behavior and may contribute to increased proliferation. While our study includes retrospective data, which may have residual confounding, we herein provide compelling evidence of an increased risk of cSCC among patients with cardiovascular disease receiving diuretics, particularly potassium-sparing diuretics. The findings suggest that while thiazide and loop diuretics may contribute to an elevated risk of cSCC through indirect mechanisms, potassium-sparing diuretics may have a more direct impact on cancer cell proliferation. Limitations of this study included the lack of risk factors for cSCC, including sun exposure, Fitzpatrick skin type, and geography. Future studies may investigate the effect of commonly used cardiovascular medications, especially concerning keratinocytic carcinoma development and further expand to murine models to better understand the pathophysiologic underpinnings at play. The authors have nothing to report. This was a nonhuman subject study utilizing de-identified electronic health records. Thus, Institutional Review Board approval was not required, and patient consent was not applicable. The authors declare no conflicts of interest. Supporting Information are available via Mendeley, doi: 10.17632/fkjn7xghhg.1. Ma, Kevin Sheng-Kai; Sol, Stefano; Boncimino, Fabiana; Mandinova, Anna; Chen, Steven (2026), “Supporting Information for: ‘Effect of diuretics on cutaneous squamous cell carcinoma: Clinical and translational evidence’”. Further data that support the findings of this study are available from the corresponding author upon reasonable request.
Ma et al. (Wed,) studied this question.