ERBB2 (HER2) was the top inhibited upstream regulator in noninvasive fibroblasts. (A) Flow cytometry analysis confirmed the overexpression of SEMA7A in lung fibroblasts. (B) Cell proliferation rates of fibroblasts with SEMA7A overexpression or control fibroblasts were determined by EdU assays. (C) Cell-surface expression of SEMA7A was determined by flow cytometry on single-cell homogenate of CD31⁻, CD45⁻, EPCAM⁻ cells from IPF and healthy samples. (D) Single-cell Western blot confirmed the downregulation of FOXF1 in invasive fibroblasts. (E and F) Dot plot visualization of the −Log₁₀(FDR) (E) and bar plot visualization of the Activation Z-score (F) of the top 30 activated and inhibited upstream regulators of noninvasive fibroblasts by IPA analysis. ERBB2 was the top inhibited regulators of noninvasive fibroblasts. ERBB2 was highlighted as the most inhibited regulator. (G) The regulating network of invasive fibroblasts combining canonical signaling pathways and upstream regulators showed that the core signaling pathway was the invasion of tumor cell lines, suggesting that invasive lung fibroblasts had metastatic cancer-related signatures.