Fig. 1: SENP1 is downregulated in fatty liver, deletion of SENP1 in hepatocytes causes RIPK1-dependent liver damage.

a Western blots and quantification of SENP1 expression in the livers of individuals with non-steatosis (n = 6), simple steatosis (n = 17) or NASH (n = 12). Protein expression was normalized to Tubulin levels and shown as relative values. Pearson comparison analyses of the correlation between SENP1 protein levels and NASH activity score (NAS) (b), serum alanine transaminase (ALT), and aspartate aminotransferase (AST) concentrations (c). Two-tailed Spearman’s rank correlation coefficient analysis (P = 1 × 10⁻¹⁴) (b, c). d Gross appearance of livers from 8-month-old mice of indicated genotypes. Arrows indicate liver damage and inflammation. Representative images out of n = 9 (Senp1^f/f), n = 5 (Senp1^f/f;Alb-Cre), and n = 4 (Senp1^f/f;Alb-Cre;Ripk1^D138N/D138N) mice are represented. Liver weight of indicated genotypes is shown on right. e Serum levels of ALT and AST from 8-month-old mice of indicated genotypes (n = 8 for Senp1^f/f, n = 6 for Senp1^f/f;Alb-Cre, and Senp1^f/f;Alb-Cre;Ripk1^D138N/D138N). f Immunofluorescence images of p-S166 RIPK1 of liver sections from 8-month-old mice with indicated genotypes. Representative images out of n = 8 (Senp1^f/f), n = 6 (Senp1^f/f;Alb-Cre and Senp1^f/f;Alb-Cre;Ripk1^D138N/D138N) mice are represented. Graph depicting numbers of p-S166 RIPK1⁺ cells on liver sections of indicated genotypes. g Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay was performed on liver sections from 8-month-old mice with indicated genotypes. Representative images out of n = 8 (Senp1^f/f), n = 6 (Senp1^f/f;Alb-Cre and Senp1^f/f;Alb-Cre;Ripk1^D138N/D138N) mice are represented. Graph depicting numbers of TUNEL⁺ cells on liver sections of indicated genotypes. Data are expressed as mean ± s.e.m. (a, d, e, f, g). One-way ANOVA, post hoc Dunnett’s test (a, d, e, f, g). Source data are provided as a Source Data file.