Methionine drives lung adenocarcinoma progression via regulation of BACH1-SERPINE1.

Lung adenocarcinoma is the most common histological subtype of lung cancer worldwide, yet the precise mechanisms driving its progression remain poorly understood. Methionine has been shown to promote the proliferation, migration, and invasion of lung adenocarcinoma cells. Furthermore, methionine induces the development of cancer stem cell (CSC)-like properties, which are critical for self-renewal and tumor initiation, in A549 and H460 cells. Gene expression analysis identified SERPINE1 as the primary gene upregulated in A549 cells following methionine treatment. SERPINE1, also known as serine protease inhibitor clade E member 1, functions as an inhibitor of tissue plasminogen activator and urokinase. Its involvement in the growth and progression of various cancers has been suggested. Here, we demonstrated that SERPINE1 depletion inhibited lung adenocarcinoma cell proliferation and suppressed CSC-like properties in A549 and H460 cells. This effect was reversed upon methionine supplementation. Mechanistically, the knockdown of SERPINE1 resulted in reductions in intracellular methionine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) levels in both in vitro and in vivo models, which was counteracted by the overexpression of the transcription factor BACH1. These findings suggest that a BACH1-driven SERPINE1 axis may contribute to the promotion of lung adenocarcinoma stemness by regulating methionine metabolism.