Fig. 1

HSC activation in liver metastasis and an endogenous regulation mechanism. a Heat map comparing activated and quiescent HSC (aHSC and qHSC) gene signatures between metastatic-free sites and metastatic sites in CRC liver metastasis patients. Columns represent 50 GEO patient samples grouped according to different collection sites (metastasis-free (meta-free) and metastatic site (meta site)); rows represent HSC markers sorted by different states (activation and quiescence). Values represent the log2 ratio over control (gene expression in metastasis-free samples). b Expression of RXFP1 on aHSCs in the CT26-FL3 metastatic liver. Numbers in yellow indicate the average % of α-SMA-positive cells expressing RXFP1 quantified in five randomly selected fields per mouse (n = 3). Bars in lower left and right panels represent 100 and 20 μm, respectively. c Relative RXFP1 expression in CT26-FL3 metastatic livers of PBS and pRLN LCP-treated groups as well as in CT26-FL3 cell lines were compared with healthy livers by quantitative RT-PCR (n = 6). LM liver metastasis. d, e Hepatic RXFP1 and RLN expression at different stages of MCD diet-induced NASH model (d) or CCl₄-induced liver fibrosis (e). Relative RXFP1 mRNA and RLN peptide expressions in the fibrotic livers at different stages were compared with healthy livers by quantitative RT-PCR (n = 5) and ELISA (n = 6), separately. f RLN peptide expression in the liver and serum of male and female mice bearing CT26-FL3 liver metastasis (n = 6). g Schematic of CRC liver metastasis model via hemi-splenic injection and gender disparity of the metastatic progression monitored by bioluminescence analysis (n = 5). h Differences of the incidence and survival of synchronous liver metastases from CRC (4898 males vs. 3460 females), pancreatic cancer (2708 males vs. 1718 females), and lung cancer (3001 males vs. 2256 females) in male and female patients aged 15–60 based on the clinical data (2010–2014) acquired from SEER database. Significant differences were assessed in (c−g) (each time points), and (h) left panel using t test, in (h) right panels using log rank test. Results are presented as mean (SD). *p < 0.05, **p < 0.01, ***p < 0.001, n.s., not significant