In vitro evidence and integrative bioinformatics identify the SGLT2-PPARγ axis as a target against polyethylene...

Microplastics have emerged as a growing burden to human health, with increasing evidence linking chronic exposure to adverse outcomes including inflammation, metabolic disruption, and carcinogenesis. Microplastics can be internalized by colorectal cancer (CRC) cells and influence cancer-related processes including metastasis, chemoresistance, oxidative stress, and cellular metabolism. However, the molecular mechanism underlying microplastic effects on CRC progression and metabolism remain poorly understood.

HT-29 and HCT 116 CRC cells were exposed to polyethylene (PE) microplastics (10 µg/mL) up to 72 h. Cell viability was assessed using the CCK-8 assay, and metabolic and tumorigenic features were evaluated through enzyme-linked immunosorbent (ELISA) assays and XF HS Seahorse Bioanalyzer. The modulatory effects of SGLT2 inhibitor canagliflozin (iSGLT2), γ-butyrobetaine (γBB) and L-carnitine (Cnt) on PE-induced alterations was investigated with immunoblotting, flow cytometric and bioinformatic analyses.

PE exposure enhanced proliferation (p < 0.001), inflammation, angiogenesis and invasive potential. PE also increased cellular bioenergetics, marked by heightened glycolysis and mitochondrial respiration (p < 0.05). At molecular level, upregulation of SIRT1 (p < 0.05), and SGLT2 protein expression (p < 0.05) were observed. iSGLT2 counteracted the effects of PE, by reducing cell proliferation, inflammation, mitochondrial respiration, and glycolysis (p < 0.001), while promoting lipid peroxidation and ferroptotic cell death (p < 0.001), highlighting the potential to target metabolic vulnerability of CRC cells. Similarly, PE, γBB and Cnt (PE + γBB + Cnt) ameliorated the onco-metabolic changes induced by PE and triggered ferroptotic cell death. Bioinformatic analysis identified PPARγ as a common target of CRC and iSGLT2 and was modulated by both canagliflozin and γBB + Cnt, suggesting a shared molecular mechanism.

Results unveil the adverse effects of PE on CRC progression underscoring a dynamic interplay between environmental pollutants, metabolic regulators and dietary bioactive modulators. This evidence lay the groundwork for future studies on integrative approaches aimed at mitigating the effects of microplastic pollution on CRC.