Antifibrotic therapies for metabolic dysfunction-associated steatotic liver disease

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects more than a quarter of the adult population worldwide. MASLD can progress to metabolic dysfunction-associated steatohepatitis (MASH), which is associated with increased risk of progression to liver fibrosis, cirrhosis and hepatocellular carcinoma, as well as cardiovascular complications. The pathogenesis of MASLD is complex and initiated by altered metabolic signalling circuits between the adipose tissue, muscle, gut and liver. Liver fibrosis is largely driven by the crosstalk of steatotic hepatocytes with macrophages and hepatic stellate cells and constitutes the primary determinant of outcomes in MASLD. Therefore, fibrosis regression is a key therapeutic goal for MASH therapies. Here, we review therapeutic strategies that directly or indirectly reduce liver fibrosis and discuss novel therapeutic concepts. Among these, the targeting of hepatocytes and metabolism have yielded fibrosis reduction in clinical trials and led to the first FDA-approved therapy for MASH. However, these therapies reduce fibrosis only in a subset of patients and have not yet shown benefits beyond the F2-F3 fibrosis stage. Direct antifibrotics and macrophage-based therapies may be more suitable for advanced stages of MASH, but are still in the developmental stage. The arsenal of therapies for MASLD is rapidly expanding and includes macrophage transplantation, hepatocyte-specific oligonucleotides, as well as CAR T cell-based therapies. Integrating these novel therapeutic concepts into stage-specific and/or combination therapies targeting divergent pathogenic mechanisms and cell types is the focus of ongoing research, which may lead to fibrosis reduction in a higher percentage of patients with MASH.

Keywords: HSC; Kupffer cells; NAFLD; NASH; Non-alcoholic fatty liver disease; cirrhosis; hepatocellular carcinoma; inflammation; non-alcoholic steatohepatitis; outcomes; pharmacologic; portal hypertension.

Graphical abstract

Fig. 1

Therapeutic interruption of the cellular crosstalk that promotes liver fibrosis in MASLD. Obesity, insulin resistance and dyslipidaemia increase hepatocyte steatosis, ER stress and cell death as well as activation of the YAP/TAZ pathway and NOTCH pathways. TAZ- and NOTCH-driven secretion of hedgehog ligands and OPN, as well as secretion of galectin 3 and DAMPs like P2Y14 ligand UDP-glucose may directly promote the activation of HSCs. Apoptotic bodies, mitochondrial DAMPs and other DAMPs, such as DNA and HMGB1, activate macrophages, which in turn secrete TGFβ, IL-1β and TNF to promote HSC activation and survival in MASH. Together, this may result in progressive liver fibrosis with parenchymal extinction and loss of liver function as well as the development of portal hypertension and increased risk for the development of HCC. Several therapies that target metabolism and hepatocytes, including GLP-1/GIP/glucagon RA, THRβ agonists, pan-PPAR agonists, FGF21 mimetics, as well as a large number of drugs still under investigation, may improve hepatocyte steatosis, stress, cell death and mediators that promote HSC and macrophage activation and, thereby, reverse liver fibrosis. Targeting macrophages (e.g. via chemokine receptor antagonism, inflammasome inhibitors and TLR inhibitors) and HSCs (e.g. via CAR T cells, TGFβ inhibitors, integrin inhibitors or oligonucleotide therapy) has not yet been proven to reverse liver fibrosis in patients with MASLD but remains promising. CAR, chimeric antigen receptor; DAMPs, damage-associated molecular patterns; ER, endoplasmic reticulum; HCC, hepatocellular carcinoma; Hh, hedgehog; HMGB1, high molecular group box 1; OPN, osteopontin; TGFβ, transforming growth factor β; TLR, Toll-like receptor; TNF, tumour necrosis factor.

Fig. 2

Targeting distinct HSC states in MASLD. In MASLD, HSCs exist in four main states: quiescent, activated, deactivated, and senescent. qHSCs are characterised by their homeostatic and hepatoprotective properties, expressing mediators such as HGF, RSPO3 and BMPs. Following MASH-induced liver injury, HSCs activate and proliferate and acquire fibrogenic, angiogenic, contractile, immunosuppressive and tumour-promoting properties through the expression of fibrillar collagens, non-collagenous ECM, αSMA and the loss of hepatoprotective mediators, HGF, RSPO3 and BMPs. With improved MASLD, HSCs may deactivate (dHSCs) and return to a near-quiescent state. In progressive MASLD, HSCs may undergo senescence, characterised by the "senescence-associated secretory phenotype" (SASP), with increased IL-1β, IL-6, IL-8, and TNF expression as well as lower ECM expression. HSC-directed therapeutic strategies in MASLD include the restoration of a healthy HSC balance by reducing pathogenic aHSCs and increasing protective qHSCs/dHSCs; as well as by eliminating sHSCs. aHSCs, activated HSCs; BMP, bone morphogenetic protein; dHSCs, deactivated HSCs; ECM, extracellular matrix; HGF, hepatocyte growth factor; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; qHSCs, quiescent HSCs; PLVAP, plasmalemma vesicle-associated protein; RSPO3, R-spondin 3; SASP, senescence-associated secretory phenotype; sHSCs, senescent HSCs.

Fig. 3

Macrophage states in MASLD. During MASLD progression, profibrogenic macrophage subsets (∗Ly-6c^high Trem2^low in mice, further characterisation in patients needed) promote HSC activation and survival through the secretion of TGFβ, pro-inflammatory mediators like IL-1β and TNF and through physical contact. During MASLD resolution, specific subsets of macrophages (∗Ly-6c^low Trem2^high in mice, further characterisation in patients needed) degrade ECM via high MMP expression and promote the return to homeostasis, additionally through phagocytes and the secretion of anti-inflammatory and pro-resolving lipid mediators. Shifting the macrophage balance from profibrogenic to pro-resolution may represent a strategy for the treatment of MASLD fibrosis. ECM, extracellular matrix; IL, interleukin-; MASLD, metabolic dysfunction-associated steatotic liver disease; MMPs, matrix metalloproteinases; TGFβ, transforming growth factor β; TNF, tumour necrosis factor.

Fig. 4

Stage-specific therapeutic concepts in MASLD. While early stages (F0-F1 fibrosis) may not require medical therapy, encouraging data suggest that hepatocyte- and metabolism-directed therapies may not only improve the underlying metabolic abnormalities but also achieve reversal of fibrosis by ≥1 stage in subsets of patients with F2-F3 fibrosis. In patients with cirrhosis (stage F4), hepatocyte- and metabolism-directed therapies alone seem to have little efficacy in reversing fibrosis. Instead, HSC- and macrophage-directed therapies may be more appropriate for patients with F4 fibrosis, possibly in combination with hepatocyte- and metabolism-directed therapies. HSC, hepatic stellate cell; MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease.