(A) PXS-S2A inhibition curves against LOXL2 and LOXL3 (upper panel), LOX, LOXL1, LOXL4 (middle panel), and all LOX/LOXL enzymes (lower panel). Downward arrows in (A–E, G) identify LOXL2/LOXL3-selective dose. (B–G) Lung fibroblasts from IPF patients (n = 3 donors, two experiments per donor) were used in the 3D model of fibrosis in the presence of 1 mM BAPN, PXS-S2A (at concentrations indicated) or vehicle control for 6 weeks. Bars are mean +s.e.m. (B–D) Hydroxyallysine-derived collagen cross-link analysis: (B) HLNL determined by LC-MS; (C) DHLNL determined by LC-MS; (D) Total mature (PYD +DPD) cross-links determined by ELISA. *p<0.05; **p<0.01; ***p<0.001 by one-way repeated measures ANOVA with Dunnett’s post-test. (E) Total collagen content determined by hydroxyproline assay. (F–G) Parallel plate compression testing of the 3D culture of lung fibrosis. (F) Typical stress versus strain plots following treatment with LOXL2/LOXL3 inhibitor or BAPN. (G) Young’s modulus. *p<0.05; **p<0.01 by one sample t-test. (H–J) Scatterplots showing dependency of tissue stiffness on (H) collagen content (r = −0.0272; p=0.873), (I) immature (r = 0.532; p=0.0007) or (J) mature (r = 0.753; p<0.0001) collagen cross-link density following PXS-S2A treatment (Multivariate correlation including mean tissue stiffness, normalised collagen and immature and mature cross-links).