Phase separation of PHLDB2 promotes lung adenocarcinoma progression through FLNA stabilization and ERK activation

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, but the phase separation-related mechanisms that support its progression remain poorly defined. By integrating phase separation-related gene profiling with prognostic modeling, we identified PHLDB2 as a high-risk candidate associated with poor outcome in LUAD. PHLDB2 protein expression was elevated in LUAD tissues and patient-derived tumor organoids and showed predominant cytoplasmic punctate localization. Recombinant protein assays, live-cell imaging and FRAP analysis demonstrated that PHLDB2 forms dynamic condensates through its intrinsically disordered regions. Functionally, PHLDB2 depletion suppressed adhesion-associated signaling programs and reduced LUAD cell adhesion, migration, invasion, proliferation, and xenograft tumor growth. Conversely, full-length PHLDB2 enhanced these cellular and tumor-associated effects, whereas these effects were attenuated in cells expressing IDR-deletion variants. Mechanistically, PHLDB2 colocalized and co-assembled with FLNA in condensate-like structures and was associated with increased FLNA protein stability and ERK phosphorylation. FLNA restoration partially rescued ERK activation and proliferation after PHLDB2 knockdown. These findings identify PHLDB2 as a phase separation-associated regulator of LUAD progression and suggest that it promotes malignant phenotypes partly through the FLNA-ERK signaling axis.