Fig 2: Hepatocyte-specific inhibition of IL11 cis-signaling protects mice against HFMCD diet-induced NASH.a Schematic of HFMCD feeding regimen for AAV8-Alb-Cre injected Il11ra1loxP/loxP (conditional knockout; CKO) mice for experiments shown in (b–k). Il11ra1loxP/loxP mice were intravenously injected with either AAV8-Alb-Null or AAV8-Alb-Cre to delete Il11ra1 specifically in hepatocytes 3 weeks prior to the start of HFMCD diet. b Western blots of hepatic IL11RA and GAPDH (n = 3 mice/group). c Body weight (shown as a percentage (%) of initial body weight). d Representative gross anatomy, H&E-stained (scale bars, 50 µm), and Masson’s Trichrome (scale bars, 100 µm) images of livers. Representative dataset from n = 5 mice/group is shown for gross anatomy; representative dataset from n = 4 mice/group is shown for H&E-stained and Masson’s Trichrome images. e Hepatic triglycerides content. f Serum ALT levels. g Serum AST levels. h Hepatic GSH content. i Hepatic collagen levels. j Heatmap showing hepatic mRNA expression of pro-inflammatory markers (Tnfa, Ccl2, Ccl5) and fibrotic markers (Col1a1, Col1a2, Col3a1, Acta2). Values are shown in Supplementary Fig. 8c and d. k Western blots showing hepatic ERK and JNK activation status (n = 3 mice/group). c, e–j NCD (n = 5 mice/group), HFMCD (n = 6 mice/group). c Data are shown as mean ± SD, two-way ANOVA with Tukey’s correction, statistical significance (P values) are shown for comparison between WT HFMCD and CKO HFMCD; e–i data are shown as box-and-whisker with median (middle line), 25th–75th percentiles (box), and min–max values (whiskers); two-way ANOVA with Tukey’s correction. Source data are provided as a Source data file.

Fig 3: Hepatocyte-specific inhibition of IL11 cis-signaling protects mice against WDF-induced obesity and NASH.a Schematic of WDF-fed control and CKO mice for data shown in (b–m). Three weeks following AAV8-Alb-Null or AAV8-Alb-Cre virus injection, CKO mice were fed WDF for 16 weeks. b Western blots showing hepatic levels of IL11RA and GAPDH (n = 3 mice/group). c Body weight (shown as a percentage (%) of initial body weight). d Fat mass. e Representative gross anatomy, H&E-stained (scale bars, 50 µm), and Masson’s Trichrome (scale bars, 100 µm) images of livers. Representative dataset from n = 5/group is shown for gross anatomy; representative dataset from n = 4 mice/group is shown for H&E-stained and Masson’s Trichrome images. f Hepatic triglycerides content. g Liver weight. h Serum ALT levels. i Serum AST levels. j Hepatic GSH content. k Hepatic collagen levels. l Hepatic pro-inflammatory and fibrotic genes expression on heatmap (values are shown in Supplementary Fig. 9c and d). m Western blots showing activation status of hepatic ERK and JNK (n = 3 mice/group). c, d, f–l n = 5 mice/group. c, d Data are shown as mean ± SD, two-way ANOVA with Tukey’s correction, statistical significance (P values) are shown for comparison between WT WDF and CKO WDF; f–k data are shown as box-and-whisker with median (middle line), 25th–75th percentiles (box), and min–max values (whiskers); two-way ANOVA with Tukey’s correction. Source data are provided as a Source data file.

Fig 4: IL11RA is highly expressed in hepatocytes and IL11 cis-signaling is hepatotoxic.a Immunohistochemistry staining of IL11RA and IL6R in healthy human liver sections (scale bars, 20 µm, n = 1 independent experiment, due to limited amount of human liver section). b Flow cytometry forward scatter (FSC) plots of IL11RA, IL6R, and gp130 staining and fluorescence intensity plots of IL11RA and IL6R staining on hepatocytes and THP-1. c Abundance of IL11RA1 and IL6R reads in hepatocytes at baseline based on RNA-seq (left) and Ribo-seq (right) (transcripts per million, TPM) (n = 3). d, e Read coverage of d IL11RA1 and e IL6R transcripts based on RNA-seq (gray) and Ribo-seq (red) of primary human hepatocytes (n = 3). f Western blots showing ERK, JNK, and STAT3 activation status and g ALT secretion (n = 4) by hepatocytes following a dose range stimulation of either hyperIL11 or hyperIL6. h ALT levels in the supernatants of hepatocytes stimulated with hyperIL11 alone or in the presence of increasing amounts of soluble gp130 (sgp130) (n = 4). i, j Western blots of hepatocyte lysates showing i phosphorylated ERK and JNK and their respective total expression in response to hyperIL11 stimulation alone or with sgp130 and j phospho-STAT3 and total STAT3 in response to hyperIL6 stimulation with and without sgp130. k Representative FSC plots of propidium Iodide (PI) staining of IL11-stimulated hepatocytes in the presence of sgp130 or soluble IL11RA (sIL11RA). l Western blots showing phospho-ERK, phospho-JNK, cleaved caspase-3, and their respective total expression, NOX4, and GAPDH in hepatocytes in response to IL11 stimulation alone or in the presence of sgp130 or sIL11RA. i, j, l Representative data of n = 2 independent experiments. b–l Primary human hepatocytes; f–l 24 h stimulation; hyperIL11, hyperIL6, IL11 (20 ng/ml), sgp130, sIL11RA (1 µg/ml). c, g, h Data are shown as box-and-whisker with median (middle line), 25th–75th percentiles (box), and min–max values (whiskers). g, h One-way ANOVA with Dunnett’s correction. Source data are provided as a Source data file.

Fig 5: IL11 drives NASH phenotypes through autocrine effects in lipotoxic hepatocytes and paracrine activity in hepatic stellate cells.a–l Data for palmitate (0.5 mM) loading experiment on primary human hepatocytes (24 h) in the presence of either IgG (2 µg/ml), anti-IL11RA (X209, 2 µg/ml), or sgp130 (1 µg/ml). a IL11, b IL6, c CCL2, and d CCL5 protein secretion levels as measured by ELISA of supernatants (n = 3). e Representative FSC plots and f quantification of PI+ve hepatocytes stimulated with palmitate (n = 3). g ALT levels in supernatants (n = 3). h Total and reduced hepatocyte glutathione (GSH) levels (n = 4). i Representative fluorescence images of DCFDA (2',7'-dichlorofluorescein diacetate) staining for ROS detection (scale bars, 100 µm) (n = 4 independent experiments). j Western blots of phospho-ERK, ERK, phospho-JNK, JNK, cleaved caspase-3, caspase-3, NOX4, and GAPDH. Data from two independent biological experiments are shown. k Percentage of fatty acid oxidation by Seahorse assay (n = 10). l Representative fluorescence images (scale bars, 100 µm) of ACTA2+ve cells and Collagen I immunostaining for experiment shown in Supplementary Fig. 5j (n = 2 independent experiments, 14 measurements per condition per experiment). a–d, f, g Mean ± SD; h, k data are shown as box-and-whisker with median (middle line), 25th–75th percentiles (box), and min–max values (whiskers). a–d, f–h, k One-way ANOVA with Tukey’s correction. Source data are provided as a Source data file.