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Prolyl 4-hydroxylase β-subunit (P4HB) is a class of molecular chaperones that inhibits the misfolding of endoplasmic reticulum proteins, and its role in microinvasive adenocarcinoma (MIA) progresses to invasive adenocarcinoma (IAC) is currently unclear. We mined the single-cell dataset GSE189357 to analyze the role of P4HB in LUAD progression. Subsequently, P4HB was overexpressed in H1299 and A549 cell lines, and Galactose lectin-3 binding protein (LGALS3BP) expression was increased and NF-kB pathway was inhibited by PCR and WB. Meanwhile, we also knock down of P4HB in H1299 and A549 cell lines, and the LGALS3BP was decreased and NF-kB pathway was activated. Afterward, the interaction between P4HB and LGALS3BP were verified by Co-IP assays. Meanwhile, the ferroptosis level and the cell proliferation, invasion and metastasis ability were detected under different P4HB expression. Finally, overexpression and knockdown P4HB stable transplants were constructed and verified in vivo. Overexpression of P4HB promoted LUAD cell proliferation (approximately two-fold) and consequently metastasis (approximately two-fold), while inhibiting ferroptosis development, as evidenced by halved ROS production. Clinically, increased P4HB is accompanied by a poor prognosis. Mechanistically, P4HB promotes LGALS3BP expression, suppressing NF-kB pathway activation and thereby driving LUAD progression. P4HB inhibited the activation of the NF-kB pathway by promoting the expression of LGALS3BP, thus promoting the progression of MIA to IAC. This provides a new target for the clinical diagnosis and treatment of LUAD.