Targeting OFD1 restrains KRAS-driven pancreatic cancer progression by impairing macropinocytosis

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy driven by oncogenic KRAS and characterized by profound metabolic rewiring. To sustain proliferation under nutrient stress, PDAC cells rely on macropinocytosis, an cytoskeleton-dependent pathway for extracellular nutrient uptake. The Oral-Facial-Digital syndrome 1 protein OFD1 is implicated in the progression of PDAC and regulates actin cytoskeletal dynamics. However, its role in macropinocytosis remains unclear. Here, we identify OFD1 as a key downstream effector of KRAS that orchestrates macropinocytosis. The oncogenic KRAS induces OFD1 expression, wheras OFD1 depletion markedly impairs macropinocytic activity and consequently suppresses tumor growth in KRAS mutant PDAC xenograft models. Mechanistically, OFD1 sustains NF-κB-dependent transcription of Syndecan-4 (SDC4), a core component of the macropinocytic machinery. In turn, restoration of SDC4 expression rescues macropinocytosis and tumor growth. Notably, a drug-repurposing screen identifies pharmacological degradation of OFD1 as an effective strategy to inhibit macropinocytosis and restrain PDAC progression. Consistent with these findings, OFD1 expression positively correlates with SDC4 levels in PDAC patient samples, and elevated SDC4 expression is associated with poor patient survival. Together, these findings establish OFD1 as a central regulator of macropinocytosis and reveal a potential metabolic vulnerability in PDAC.