Liver fibrosis (LF) refers to the excessive deposition and abnormal distribution of the extracellular matrix (ECM) caused by acute or chronic liver injury, which affects the prognosis of liver diseases. Activated HSCs play a central role in LF through their ability to differentiate into myofibroblasts (MFBs) and secrete ECM. Intercellular communication within the liver is important for HSC activation and LF, whether in the initial or persistent stage. Hepatocytes (HCs), the most abundant cell type in the liver, are closely related to hepatic nutrition metabolism and detoxification. Moreover, HC damage is the initiating factor of LF, and interactions between HCs and HSCs may be the most critical event involved in the process of LF. This article reviews the intercellular communication between HCs and HSCs based on paracrine effects, extracellular vesicles, and inflammasomes, which is expected to lead to the development of effective antifibrotic strategies. Export

Pyroptosis is a novel programmed cell death that exists in inflammatory diseases and methyltransferase-like 3 (METTL3) is a core N6-methyladenosine (m6A) modified methyltransferase that has been shown to regulate cell fate. However, the role of pyroptosis in acute liver injury (ALI) is still unknown and whether it is regulated by m6A modification needs to be elucidated. Here, Mettl3 mutant and Nlrp3 knockout mouse were constructed, CCl₄- and TAA-induced ALI models were established and primary cells were isolated, and cell pyroptosis and m6A modification were evaluated. We found that hepatocyte pyroptosis is a key characteristic of ALI, and METTL3-mediated m6A modification was upregulated in hepatocytes during ALI. Inhibition of METTL3-mediated m6A modification alleviated hepatocyte pyroptosis and ALI. Through MeRIP-seq analysis and verification, Dlgap5 was determined as the target of METTL3-mediated m6A modification, which was regulated in an IGF2BP2-dependent manner. Mechanistically, METTL3 can bind to DLGAP5, and then DLGAP5 promoted pyroptosis through NF-κB-dependent NLRP3 inflammasome activation and direct potentiation of inflammasome structure formation and assembly. Mettl3 mutation or AT9283-mediated DLGAP5 inhibition alleviated pyroptosis and ALI. The effects of hepatocyte pyroptosis on cell interaction were then explored and we revealed that NLRP3 inflammasome and interleukin releasing by the GSDMD-N-dependent membrane pores from pyroptotic hepatocytes activated macrophage metabolic reprogramming and M1 polarization, further exacerbating ALI. Nlrp3 deficiency alleviated ALI by suppressing hepatocyte pyroptosis and blocking communication between macrophages and hepatocytes. Our findings indicate the potential mechanisms of ALI from an intercellular communication perspective, and targeted-inhibition of DLGAP5 and -blockade of hepatocyte-macrophage interaction provide promising strategies for ALI treatment.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 ⁺ LSECs promote the recruitment of CD63 ⁺ monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.