Exploring the role of PNPLA3 I148M in cancer using the selective small molecule degrader NUV-244

The patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant is a well-established genetic determinant of fatty liver disease, yet emerging evidence suggests broader implications in cancer biology, particularly in hepatocellular carcinoma and metabolic reprogramming of tumor cells (Tavaglione et al., 2024). We recently identified NUV-244 as a potent and selective small-molecule degrader of PNPLA3 I148M (Steigemann et al., 2025). These findings provided the first pharmacological and molecular framework to directly interrogate PNPLA3 I148M´s function in liver cells. Building upon these insights, we sought to investigate the potential oncogenic or tumor-modulatory role of PNPLA3 I148M in cancer, and to evaluate how pharmacologic inhibition by NUV-244 influences cancer cell metabolism, proliferation, and survival. We performed a comparative analysis of cancer cell lines harboring endogenous PNPLA3 I148M mutations versus wild-type counterparts and generated isogenic cell line models using a PNPLA3 I148M overexpression approach. These models were used to assess transcriptomic and proteomic modulation, mitochondrial function and cell viability with and without NUV-244 treatment. Using these experimental systems, we aim to define how PNPLA3 I148M contributes to cancer cell metabolic plasticity and whether its pharmacologic inhibition creates selective vulnerabilities. In summary, these studies establish a mechanistic basis for PNPLA3 I148M´s potential role in tumor biology and highlight NUV-244 as a chemical tool to probe its function in cancer.