Immunopathogenic mechanisms and immunoregulatory therapies in MASLD

“For example, seminal work has demonstrated that obesity is associated with marked in fi ltration of proin fl ammatory macrophages into adipose tissue, which is correlated with insulin resistance and low-grade systemic in fl ammation [148, 149].”

“For example, seminal work has demonstrated that obesity is associated with marked in fi ltration of proin fl ammatory macrophages into adipose tissue, which is correlated with insulin resistance and low-grade systemic in fl ammation [148, 149].”

“Neutrophils are the most abundant leukocytes in the blood and form a critical arm of innate immunity, playing a well-recognized role in antibacterial defense by extruding a meshwork of chromatin fi bers to establish neutrophil extracellular traps (NETs) via a process known as NETosis [63, 64].”

“These concerns led to a multi-stakeholder effort to develop a consensus on a change in nomenclature and the diagnostic criteria for the condition [7, 8].”

“Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly named nonalcoholic fatty liver disease (NAFLD), affects approximately 30% of the global population, leading to a major health and economic burden [1].”

“These concerns led to a multi-stakeholder effort to develop a consensus on a change in nomenclature and the diagnostic criteria for the condition [7, 8].”

“N 6 -methyladenosine (m 6 A), the most abundant RNA modi fi cation in eukaryotic cells, affects various biological functions and diseases [123], and it has been reported to regulate myeloid cell activation via MASLD.”

“The cyclic GMP ‒ AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, a key mediator of in fl ammation, has emerged as a critical mechanism for sensing and regulating the cellular response toward microbial and host-derived DNAs [129].”

“Innate lymphoid cells (ILCs), which are based on developmental and functional trajectories, can be divided into fi ve subsets: natural killer (NK) cells, ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells [87].”

“…a once-weekly injectable GLP-1R agonist, resulted in signi fi cant weight loss, histological resolution of steatohepatitis and improvements in cardiovascular biomarkers [184], although it did not meet the histological anti fi brotic effect threshold or reverse cirrhosis in a separate study [185].”

“Accumulating evidence supports the concept that ballooned hepatocytes, a de fi ning feature of steatohepatitis, generate a secretome that induces in fl ammatory and fi brogenic responses in neighboring cells [15].”

“E2F2, a crucial member of the E2F family, plays an important role in regulating cell proliferation, differentiation and apoptosis [104].”

“In 2019, via index and transcriptional single-cell sorting, a novel and conserved Trem2 + LAM subset was identi fi ed in both mouse and human livers during obesity [35].”

“Recently, mitochondrial DNA (mtDNA) has been recognized as an endogenous damage-associated molecular pattern (DAMP), thus activating the innate immune response and promoting in fl ammation after release into the cytosol and circulation [130].”

“Semaglutide is currently undergoing phase III trials for MASLD with fi brosis and compensated MASH cirrhosis; interim results show a signi fi cant improvement in fi brosis for the noncirrhotic population at 72 weeks [186].”

“…in regulating blood glucose levels, lipid metabolism, and several other critical biological functions by interacting with the GLP-1 receptor (GLP-1R), which is a vital component of the G protein-coupled receptor (GPCR) family and is expressed primarily on the surfaces of various cell types [177].”

“Owing to recent technological advances, including the application of scRNAseq and spatial transcriptomics to mouse models, we now know that the population of EmKCs is depleted during MASLD development and is replaced by distinct subsets of bone marrow-derived macrophages [29, 46].”

“Notably, MASH could soon be the top indication for liver transplantation across all subgroups if the current estimates for the increase in MASH remain [21].”

“…’ t-eat-me ” signal cluster of differentiation 47 (CD47), a transmembrane glycoprotein expressed on the surface of various cell types, prevents the inadvertent phagocytosis of live cells owing to CD47-mediated activation of the signal-regulatory protein α (SIRP α ) receptor on myeloid cells [134].”

“The causative role of ATMs in systemic metabolic derangements is further supported by studies showing that genetic or pharmacological ablation of ATMs normalizes whole-body insulin sensitivity [152].”

“A Trem2 + MASH-associated macrophage subset, which is a feature of mouse and human MASH that is linked to disease severity, was subsequently identi fi ed [36].”

“Its function in macrophages was fi rst identi fi ed in 2006, revealing that Trem2 plays a crucial role in restraining macrophage activation [34].”

“NKT cells are much more abundant in mouse livers than in human livers, and they promote MASH, fi brosis, and carcinogenesis in experimental models [91].”

“Owing to recent technological advances, including the application of scRNAseq and spatial transcriptomics to mouse models, we now know that the population of EmKCs is depleted during MASLD development and is replaced by distinct subsets of bone marrow-derived macrophages [29, 46].”

“…stress, mitochondrial dysfunction, and oxidative stress culminate in hepatocyte injury, leading to apoptosis, necrosis, and necroptosis and the release of damage-associated molecular patterns (DAMPs) and proin fl ammatory mediators that drive immune cell in fi ltration and liver in fl ammation [138].”

“Epigenetic regulation is a mechanism that modulates heritable gene expression without altering the DNA sequence and includes chromatin remodeling, histone modi fi cations, and noncoding RNA (ncRNA) regulation, among other mechanisms [108].”

“More than a decade ago, the concept of immunometabolism was proposed to elucidate the intricate interplay between metabolism and immunity [96].”

“Although GDF15 is a promising target for obesity [160, 161], the function and cellular source of GDF15 during MASLD are not fully understood.”

“Survodutide, a GLP-1/glucagon dual agonist, resulted in signi fi cant weight loss and histological MASH resolution as well as fi brosis improvement after one year of treatment [189].”

“These speci fi c CD8 + T cells are more susceptible to metabolic stimuli (including acetate and extra-cellular ATP), triggering autoaggression in an IL-15-induced FOXO1-dependent manner during MASH development [81].”

“This phenomenon mirrors the critical role of the gut vascular barrier, where the integrity of this barrier is crucial for preventing systemic in fl ammation and maintaining metabolic homeostasis [156, 157].”

“…highly expressed in the liver and intestine, can regulate the expression of genes involved in the pathogenesis of MASH by regulating cholesterol and bile acid homeostasis, hepatic gluconeogenesis, lipogenesis, intestinal barrier integrity, bacterial translocation and the gut microbiota [192, 193].”

“Sterol regulatory element binding protein cleavage-activating protein (SCAP) is a cholesterol sensor that functions to affect intracellular cholesterol homeostasis [106].”

“TREM2 was fi rst cloned from human PBMCs in 2000 [32, 33].”

“…downregulates 2553 enhancers related to the KC signature, whereas only 365 KC signature enhancers are upregulated, which is demonstrated by the differential distribution of H3K27ac, suggesting a vital role of histone acetylation in reprogramming the KC enhancer landscape under MASH conditions [40].”

“Accelerating evidence suggests that the metabolic reprogramming of immune cells plays essential roles in the pathogenesis of MASLD [97].”

“…cells, leading to proteolytic cleavage of the Notch receptor and release of the Notch intracellular domain (NICD), which subsequently translocates to the cell nucleus, where it complexes with the CSL-type DNA binding proteins CBF1 (RBPJ), Su(H), and Lag-1 to regulate gene expression [126].”

“Furthermore, these MoKCs are partly immature and exhibit a proin fl ammatory status compared with EmKCs [49].”

“Accumulating studies suggest that aspirin exerts anti-in fl ammatory and antitumor effects by inhibiting cyclooxygenase-2 and platelet-derived growth factor signaling, representing a promising and low-cost strategy for the treatment of MASLD [207 – 209].”

“In addition, NETs are able to promote the differentiation of regulatory T cells (Tregs), which contribute to carcinogenesis in MASLD [76], whereas activating PPAR α can reduce NET formation in a high-fat diet (HFD) context [111].”

“KCs are iron storage cells that play a key role in iron metabolism [54].”

“Strikingly, mtDNA from lipotoxicity-induced hepatocytes induced TNF-α and IL-6 expression in Kupffer cells, whereas STING de fi ciency attenuated this in fl ammation, suggesting that STING functions as a mtDNA sensor in Kupffer cells, contributing to MASH progression [131].”

“…much interest because of its importance and heterogeneity. β -Arrestin 2, a multifunctional adaptor protein for the desensitization and internalization of G protein-coupled receptors (GPCRs) [99], was found to be elevated in liver macrophages and circulating monocytes in patients with MASH.”

“…disease ” to “ steatotic liver disease ” , which includes all conditions characterized by abnormal hepatic lipid accumulation and encompasses MASLD, alcohol-associated liver disease (ALD), metabolic dysfunction, alcohol-associated liver disease (MetALD) and other rare causes of liver steatosis [9].”

“Ccr2 − / − mice, which lack hepatic LAMs, exhibit exacerbated MASH [28].”

“Investigating cell ‒ cell ligand ‒ receptor interactions and obesity-enriched signaling pathways in white adipose tissue (WAT) [154] highlighted a dramatic shift from immunoregulatory mechanisms in lean WAT to the establishment of in fl ammatory networks in obese WAT.”

“Activating transcription factor 3 (ATF3), a stress-induced transcription factor that binds to the cyclic AMP response element (CRE), plays a vital role in metabolic regulation and immunity [101].”

“These macrophages produce elevated levels of cytokines in culture, establishing a clear link between adipose tissue in fl ammation and advanced liver disease [153].”

“…in MASLD is rarely linear in its development and progression; rather, it fl uctuates between fl ares and resolution, which may explain why the highly dynamic parameter of in fl ammation is a weaker prognostic feature than fi brosis when it is captured at a single time point via liver histology [172].”

“Lani fi branor is a pan-PPAR agonist that modulates key metabolic, in fl ammatory, and fi brogenic pathways in the pathogenesis of experimental MASH models [200].”

“For example, central GLP-1R activation inhibits Toll-like receptor agonist-induced in fl ammation, thus reducing the severity of polymicrobial in fl ammation [180].”

“Although GDF15 is a promising target for obesity [160, 161], the function and cellular source of GDF15 during MASLD are not fully understood.”

“In addition, it has been reported that miR-223 also mediates the function of neutrophils in spontaneous resolution of liver fi brosis [118].”

“Hepatocyte-derived sphingosine-1 phosphate (S1P) was also shown to induce Trem2 expression in macrophages [39].”

“The complicated progression of MASLD extends beyond the liver, driven by the “ gut ‒ liver axis ” , where diet and genetic and gut ‒ liver interactions affect disease outcomes [164].”

“Strikingly, Trem2 -de fi cient macrophages release exosomes that impair hepatocytic mitochondrial structure and energy supply due to their high content of miR-106b-5p, which blocks Mitofusin 2 (Mfn2) expression in MASLD [38].”

“Although a role of CD4 + T cells in MASLD has been suggested [72], the exact polarization state of these cells during MASLD development remains obscure.”

“…population (KC1) and a minor CD206 high ESAM + population (KC2), only KC2-expressing genes are involved in liver metabolism regulation, including fatty acid metabolism both in steady-state and in diet-induced obesity in mice, as well as steatosis induction via the fatty acid transporter CD36 [52].”

“Experimental evidence supports pro fi brogenic functions in chronically injured livers, and inhibiting MAIT cells promotes fi brosis regression via the induction of a repair phenotype in hepatic macrophages [93 – 95].”

“Notch signaling is a highly conserved pathway that serves as the primary juxtacrine signaling pathway used for direct cell-to-cell communication between adjacent cells, in fl uencing numerous cell fate decisions in the development of multicellular organisms [125].”

“The majority of hepatic MASH macrophages are derived from recruited bone marrow-derived macrophages, which have diverse functions, as they adapt their phenotype ( “ polarization ” ) in response to the local environment [57].”

“Given the strong induction of Trem2 expression during MASH, circulating levels of soluble Trem2 (sTrem2) in MASH were demonstrated to correlate with disease severity in mice and humans [37].”

“…analysis revealed that CD69 + CD103 - CD8 + tissue-resident memory (Trm) cells were enriched in the livers subjected to MASH resolution, which attracted hepatic stellate cells in a CCR5-dependent manner and resulted in HSC apoptosis, thereby promoting MASH-related liver fi brosis resolution [82].”

“In addition, dual and triple incretin agonists that combine GLP-1 with glucagon or GIP (glucose-dependent insulinotropic polypeptide) activity to enhance metabolic effects are being developed [187].”

“B-cell de fi ciency mitigated MASH progression, and adoptively transferring B cells for MASH livers recapitulated the disease [84].”

“In the past decade, numerous FXR agonists have been assessed for the treatment of MASH, although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose limiting, as summarized in a previous review [192].”

“Owing to substantial underreporting and little recognition of the effect of alcohol on SLD, a more accurate prognose and effective management of SLD, addressing both metabolic and alcohol-related factors is crucial to appropriately diagnose, manage, and address the disease [222, 223].”

“…clinical trial (NCT05006885) revealed that pemvidutide, a GLP-1/glucagon dual receptor agonist, may be an effective treatment for MASH, as pemvidutide treatment signi fi cantly reduced liver fat content, noninvasive biomarkers of liver in fl ammation, and body weight compared with placebo [188].”

“The de fi ciency of UCP1 led to elevated extracellular succinate in liver tissue, thereby driving in fl ammation via succinate receptor 1 (SUCNR1) in liver-resident stellate cells and macrophage populations [158].”

“…extracellular vesicles (EVs) facilitate monocyte adhesion via integrin β 1 (ITG β 1)- dependent pathways [140], whereas IRE1A activation in hepatocytes induces the release of ceramide-enriched EVs, which further recruit monocyte-derived macrophages and exacerbate liver in fl ammation [141].”

“A previous study revealed that IL-22 reversed neutrophil-derived reactive oxygen species and the activation of stress kinases via the induction of metallothionein in hepatocytes, ultimately ameliorating MASH [212].”

“…-de fi cient mice are resistant to diet-induced metabolic disorders, as evidenced by fewer hepatic foamy macrophages, reduced in fl ammation, improved glucose tolerance and hepatic lipid metabolism [61], suggesting that blocking MSR1 signaling could be a promising approach for the treatment of MASLD.”

“To date, the ef fi cacy of agents that directly target immune cell function and recruitment is still lacking, since the dual CCR2/CCR5 inhibitor cenicriviroc did not demonstrate anti fi brotic ef fi cacy after 1 year of treatment in MASH patients with liver fi brosis in a phase III trial [176].”

“Fibroblast growth factor 21 (FGF21), an endocrine FGF primarily produced in the liver, protects against MASH [50].”

“However, neutrophils can also be pathogenic by releasing various in fl ammatory mediators, including different cytokines, myeloperoxidase (MPO), reactive oxygen species (ROS), and proteases [65].”

“Furthermore, in a multicenter proteomic study, a composite model comprising four proteins (ADAMTSL2, AKR1B10, CFHR4 and Trem2), body mass index and type 2 diabetes mellitus status was used to identify at-risk MASH [43].”

“Mechanistically, NKp46/NCR1, a speci fi c marker of NK cells, mediates the killing of human and mouse HSCs through unknown ligands, thus resulting in the attenuation of liver fi brosis [88].”

“Recently, GLP-1 receptor (GLP-1R) and its agonists have garnered widespread attention in the medical community because they are highly potent treatments for obesity and type 2 diabetes [178].”

“Among these miRNAs, miR-223 is broadly recognized as a protective factor in MASLD via myeloid cell-to-hepatocyte communication by targeting several in fl amma-tory genes and oncogenes in hepatocytes to prevent MASH and MASLD-HCC [116, 117].”

“Accumulating studies suggest that aspirin exerts anti-in fl ammatory and antitumor effects by inhibiting cyclooxygenase-2 and platelet-derived growth factor signaling, representing a promising and low-cost strategy for the treatment of MASLD [207 – 209].”

“…lymphocyte recruitment is mediated by distinct chemokine axes, including the CXCR6 ‒ CXCL16 pathway for natural killer T (NKT) cells, the CXCR3 ‒ CXCL9 ‒ CXCL10 pathway for in fl ammatory hepatic CXCR3 + Th17 (ihTh17) cells, and the CCR2 ‒ CCR5 signaling pathway for γδ T cells [74, 144, 146, 147].”

“Neutrophils are the most abundant leukocytes in the blood and form a critical arm of innate immunity, playing a well-recognized role in antibacterial defense by extruding a meshwork of chromatin fi bers to establish neutrophil extracellular traps (NETs) via a process known as NETosis [63, 64].”

“Although Tregs support tissue function and tissue homeostasis by limiting in fl ammation and promoting repair [75], the functions of Tregs in MASLD initiation and progression are not fully understood.”

“Among these miRNAs, miR-223 is broadly recognized as a protective factor in MASLD via myeloid cell-to-hepatocyte communication by targeting several in fl amma-tory genes and oncogenes in hepatocytes to prevent MASH and MASLD-HCC [116, 117].”

“A recent study indicated that macrophage heterogeneity in livers undergoing MASH regression closely mirrors that of active MASH [25].”

“For example, high-fat diet-induced ATM activation triggers the upregulation of proin fl am-matory gene expression in mouse models [151].”

“IL-22 functions as a tissue-protective cytokine during liver injury by activating STAT3 in hepatocytes through a receptor complex composed of IL-22R1 and IL-10R2 [211].”

“Treating MASH mice with miR-690 inhibited hepatic steatosis, fi brosis and in fl ammation [119].”

“Another example of a “ metabolic drug ” is denifanstat, an oral fatty acid synthase (FASN) inhibitor, which led to statistically signi fi cant improvements in disease activity, MASH resolution, and fi brosis in a multicenter, double-blind, randomized, placebo-controlled phase 2b trial [175].”

“Mechan-istically, Areg can activate pro fi brotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling and promote hepatocyte gluconeogenesis via IL-6 [79].”

“In human liver biopsies, the accumulation of macrophages is closely associated with the severity of MASH and fi brosis [26].”

“Neutrophil in fi ltration and NET formation are increased during the development of MASLD [68, 69], and NETs reportedly promote MASH by inducing metabolic reprogramming of HSCs [68].”

“…regulating cell growth and survival, particularly under various stress conditions, and its transcripts are m 6 A-decorated to decrease its mRNA stability, leading to reduced protein levels of DDIT4, whereas the induction of DDIT4 can mitigate MASLD by reducing macrophage effector function [124].”

“FFAR1 and 4 are activated by medium-and long-chain free fatty acids and are putative targets for the treatment of type 2 diabetes by facilitating the secretion of glucose-stimulated insulin and the release of GLP-1 [203, 204].”

“…including chromatin structure and chromatin stability, are involved in the role of immune cells in MASLD is largely unknown, but newer technologies, such as 5 C, Hi-C, Micro-C, DNAse-Hi-C, Chia-PET, HiChIP, and Plac-seq, are expected to decipher the understanding of chromosome conformation [122].”

“Furthermore, genetic or therapeutic depletion of systemic or gastrointestinal B cells ameliorated T-cell-driven in fl ammation and fi brosis in MASH by inhibiting the IgA-FcR γ signaling axis on hepatic macrophages [170].”

“Many clinical trials have assessed the use of GLP-1R agonists for obesity and type 2 diabetes [183].”

“Another phase 2, single-center randomized trial (NCT03459079) also demonstrated that lani fi branor treatment signi fi cantly reduced hepatic steatosis and improved hepatic, muscle and adipose tissue insulin resistance in patients with type 2 diabetes and MASLD [202].”

“Liver macrophages play a central role in MASLD, in fl uencing in fl ammation, fi brosis progression, and resolution [24, 25].”

“Interestingly, in a phase 2 randomized clinical trial (NCT04031729) of 80 individuals with MASLD, 6 months of daily low-dose aspirin signi fi cantly reduced hepatic fat quantity compared with placebo, but the fi ndings are preliminary and require con fi rmation in a larger population [210].”

“In addition to MASH, Trem2 + LAMs have been identi fi ed in various liver injury models, including acetaminophen (APAP)- and carbon tetrachloride (CCl 4 )- induced liver damage, where they play crucial roles in the ef fi cient clearance of dying cells [30].”

“Experimental evidence supports pro fi brogenic functions in chronically injured livers, and inhibiting MAIT cells promotes fi brosis regression via the induction of a repair phenotype in hepatic macrophages [93 – 95].”

“Although the fi rst pharmacotherapeutic for MASLD and MASH, resmetirom, has been approved for clinical use [224], we expect more targeted treatments owing to the modest ef fi cacy of resmethrin [2].”

“MS4A7, a Trem2 + MASH-associated macrophage-speci fi c pathogenic factor, exacerbated MASH progression in mice by inducing NLRP3 in fl ammasome activation via direct physical interaction, indicating that the LD-MS4A7-NLRP3 in fl ammasome axis is a key pathogenic driver of MASH progression [45].”

“…lymphocyte recruitment is mediated by distinct chemokine axes, including the CXCR6 ‒ CXCL16 pathway for natural killer T (NKT) cells, the CXCR3 ‒ CXCL9 ‒ CXCL10 pathway for in fl ammatory hepatic CXCR3 + Th17 (ihTh17) cells, and the CCR2 ‒ CCR5 signaling pathway for γδ T cells [74, 144, 146, 147].”

“Hepatic overexpression of Cxcl1 and IL8 accelerated the transition from steatosis to MASH in HFD-fed mice and was associated with marked neutrophil in fi ltration and hepatocyte death [67].”

“Consequently, the serum NE or NE-to-AAT ratio is commonly used as a biomarker to assess MASLD severity [71].”

“Neutrophils can produce various subtypes of EVs containing proin fl ammatory miRNAs or anti-in fl ammatory miRNAs [115].”

“FXR, like other bile acid receptors, is also expressed in various innate immune cells, such as monocytes and macrophages, dendritic cells, and NK and NKT cells, thus modulating several aspects of innate immunity [194].”

“Moreover, macrophage-speci fi c Scap deletion ameliorated metain fl ammation and ectopic lipid deposition by promoting the release of in fl ammatory mediators by recruiting STING and tank-binding kinase 1 to the Golgi to activate the NF-κ B signaling pathway [107].”

“However, in the context of obesity, NK cells may also support in fl ammation and alter metabolism via the induction of hepatic ER stress via osteopontin production and other mechanisms [89].”

“In addition to lipid metabolism in Kupffer cells, the activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells promotes glycolysis via the formation of complexes between β - arrestin 2 and key glycolytic enzymes, ultimately inhibiting in fl ammation and ameliorating MASLD [98].”

“Moreover, the gut microbiota is involved in the protective effects of time-restricted feeding (TRF) in MASLD via the production of 2-hydroxy-4-methylpentanoic acid (HMP), and oral supplementation with HMP alleviated in fl ammation and fi brosis in a MASH model [169].”

“…that IL-22 resolved MASLD via the entry of IL-22R1 but not hepatic IL-22R1, as demonstrated by the fi nding that hepatocyte-speci fi c Il22r1 ablation still responded to IL-22 therapy, resulting in reduced body and liver weights, decreased liver damage, and decreased collagen accumulation [213].”

“…histologic features of NAFLD activity scores (NASs), such as steatosis, lobular in fl ammation, and ballooning, but only weakly with fi brosis stage, suggesting that sTrem2 in plasma may be a noninvasive biomarker that can rule-in or rule-out the presence of MASH with elevated liver stiffness [42].”

“Overnutrition with a poor-quality diet rich in glucose, high-fructose corn syrup and saturated fat leads to increased intrahepatic triglyceride levels, which are characteristic of MASLD, through multiple pathways [14].”

“Furthermore, hepatocyte senescence exacerbates this in fl ammatory cascade through the senescence-associated secretory phenotype (SASP) [139].”

“These signals activate macrophages through the STING pathway, leading to the upregulation of the expression of proin fl amma-tory cytokines (IL-1 β , IL-6, IL-10, and TNF-α ) and increased expression of Ly6c2, a key marker of in fl ammatory monocyte recruitment [142].”

“For example, the expression of the immune regulator PU.1 is increased in the liver, primarily in macrophages, of obese mice and people, and pharmacologic PU.1 inhibition results in improved metabolic dysfunction in HFD-fed mice [18].”

“…via the reduction of cellular glucose levels via the inhibition of head box 1 (FoxO1)-mediated gluconeogenesis and the induction of free fatty acid (FFA) uptake by CD36, suggesting that ATF3 improves glucolipid metabolism in liver macrophages, ultimately protecting against MASH development [102].”

“However, as the disease progresses toward MASH, Gdf15 expression is induced in the liver, and hepatocytes, rather than macrophages, become its primary source [162].”

“Therefore, a range of conserved markers, including VSIG4, TIM4, and FOLR2, may help to distinguish EmKCs from MoKCs in MASLD [51].”

“However, analysis of these multimodal datasets is currently a major area of focus in the fi eld [215].”

“Ursolic acid was shown to target secreted phosphoprotein 1 (SPP1) to regulate Th17 cells, thus improving immune in fl ammation in MASLD [20].”

“The anti-in fl ammatory effects of GLP-1 in lung injury have also been summarized elsewhere [182].”

“Treatment with β CD-PRX effectively mitigated MASH-related liver fi brosis by decreasing cholesterol accumulation and the pro fi brotic activation of macrophages surrounding dead hepatocytes with cholesterol crystals without affecting hepatic and serum levels of cholesterol [62].”

“Targeting β -arrestin 2 in myeloid cells may be a potential strategy for MASH treatment [100].”

“Fibroblast growth factor 21 (FGF21) is an endogenous liver-secreted hormone that has therapeutic potential for treating obesity, type 2 diabetes, and MASLD [190].”

“Neutrophil elastase (NE), a serine protease secreted by neutrophils during in fl ammation via the degranulation process, plays a signi fi cant role in the pathogenesis and progression of MASH [70].”

“This loss coincided with the breakdown of vascular integrity in adipose tissue, a key event linked to the worsening of metabolic dysfunction and liver disease [155].”

“…in controlling KC death in MASLD, as evidenced by the fact that HIF-2 α decreases lysosomal and phagocytic gene expression in KCs by inducing mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation [48].”

“Owing to substantial underreporting and little recognition of the effect of alcohol on SLD, a more accurate prognose and effective management of SLD, addressing both metabolic and alcohol-related factors is crucial to appropriately diagnose, manage, and address the disease [222, 223].”

“…(EFHD2) was also signi fi cantly increased in hepatic macrophages/ monocytes from both patients and mice with MASH, which contributed to liver macrophage/monocyte reprogramming in MASH, whereas targeted EFHD2 inhibition via a hydrocarbon-stapled peptide effectively attenuated disease in mice [19].”

“…to decrease hepatic leukocyte in fi ltration, especially that of MoMFs, to dampen fi brosis development in diet-induced MASLD, which was associated with the reversal of diet-induced unfavorable changes in microbiota composition and a subsequent reduction in the translocation of TLR4 ligands [167].”

“Furthermore, another study demonstrated that B-cell-depleted mice were only partially protected from MASH, whereas B-cell-harboring but antibody-de fi cient IgMi mice were fully resistant to MASH [83].”

“Although the immunoregulatory role of FXR in MASLD has not been clari fi ed, myeloid cells have been reported to mediate the hepatoprotective effects of pharmacological FXR agonists in sclerosing cholangitis [195].”

“Importantly, in addition to macrophages, cytotoxic T cells in visceral adipose tissue (VAT) are considered critical regulators of MASH pathogenesis, which links adipose tissue in fl ammation to liver disease [163].”

“IL-17A then induces hepatocytes to release chemokines, which recruit proin fl amma-tory myeloid cells into the liver [86].”

“Over the past decade, high-resolution methods, such as single-cell RNA sequencing (scRNAseq), single-nuclear RNA sequencing (snRNAseq), spatial transcriptomics, and spatial proteogenomics, have substantially increased our knowledge of different macrophage subsets [27].”

“Of particular importance is the new category of individuals with MetALD, whose diagnosis of hepatic steatosis requires the presence of cardiometabolic risk factors (CMRFs) and daily alcohol intake between 20 – 50 g/day for women and between 30 – 60 g/day for men [11, 12].”

“The “ multiple hit ” hypothesis has emerged as the dominant theory in recent years, indicating the collective impact of immunological mechanisms in the liver, intestines, and adipose tissue on the progression of MASLD [13].”

“…aiming at ameliorating metabolic dysfunction-driven stress and injury in hepatocytes, these potential “ MASH therapies ” also inhibit the immune cell-mediated in fl ammatory response deletion of Il33 in mice ameliorated metabolic disorders, in fl ammation, and fi brosis associated with MASLD [165].”

“The regression livers were dominated by the LAM subpopulation [25, 41].”

“Additionally, lipid accumulation results in persistent NK cell dysfunction via histone hypoacetylation, and impaired functions are also observed in liver NK cells from HFD-fed mice [112].”

“…MASLD progression by ameliorating macrophage in fl ammation and coordinating macrophage actions on hepatocytes and HSCs to alleviate steatohepatitis and fi brosis [120]. miR-142a-3p is another miRNA that is essential for the functions of macrophages, whose secretion is regulated by Notch1 signaling.”

“Interestingly, there are sex and sex differences in the prevalence of MASLD, and potential sex differences in innate immune cell types have been suggested to affect its development [17].”

“Another study con fi rmed that anti-CD47 antibody treatment did not affect mouse body weight, fat mass or liver steatosis but markedly reduced liver immune cell in fi ltration and fi brosis [137].”

“…opportunity to advance our understanding and management of MASLD, such as tabular medical data analysis, multiomics data analysis, the generation of synthetic patient data, enhancing the medical imaging fi eld for MASLD, and advancing personalized medicine approaches for MASLD [216, 217].”

“For example, the fi rst FDA-approved drug is an oral, liver-directed thyroid hormone receptor beta-selective agonist that plays a key role in regulating lipid metabolism, cholesterol synthesis, and fatty acid oxidation [173, 174].”

“However, the identity of KC2 is currently debated in the fi eld because of its close transcriptomic pro fi le to that of liver sinusoidal endothelial cells (LSECs) [51, 53].”

“Immunological studies on the pathogenesis of MASLD have revealed the key role of macrophages, whereas neutrophils have received less attention [218].”

“…that obesity-related expansion of adipose tissue is associated with in fi ltration and activation of immune cells, especially adipose tissue macrophages (ATMs), which also contribute to MASLD progression since their proin fl ammatory cytokine repertoire leads to the adipose tissue secretome [159].”

“However, EmKC death is not required for bone marrow-derived macrophage in fi ltration in MASLD [47].”

“Moreover, the functions of noncoding RNAs (ncRNAs), particularly microRNAs (miRNAs), have been widely studied in MASLD [113, 114].”

“Interestingly, among these cells, only those with a Th17 polarization state were enriched in patients with MASH-related fi brosis, providing the rationale to target CD4 + T cells with a Th17 polarization state to inhibit MASH-related fi brosis development [73].”

“In patients with MASH and liver fi brosis (stages F1--F3), there was an apparent bene fi cial effect of icosabutate on surrogate histological endpoints, particularly fi brosis improvement, although the prespeci fi ed primary endpoint of MASH resolution without worsening of fi brosis was not met [206].”

“…Neutrophil extracellular trap formation, M1 macrophages polarization, and T-cell imbalance contribute to hepatic inflammation and fibrosis, 38 while the same mechanisms also drive vascular inflammation, foam cell formation, and plaque instability, linking systemic immune activation to…”