Programmed Cell Death in Liver Fibrosis

Abstract

Programmed cell death (PCD) is a comprehensive term that encompasses various forms of cell death, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy, which play a crucial role in the pathogenesis of liver fibrosis. PCD facilitates the elimination of aberrant cells, particularly activated hepatic stellate cells (HSCs), which are the primary producers of extracellular matrix (ECM). The removal of HSCs may impede ECM synthesis, thereby mitigating liver fibrosis. As such, PCD has emerged as a promising therapeutic target for the development of novel drugs to treat liver fibrosis. Numerous studies have been conducted to investigate the underlying mechanisms of PCD in the elimination of activated HSCs and other aberrant liver cells in fibrotic liver tissue, including hepatocytes, hepatic sinusoid endothelial cells (LSECs), and Kupffer cells (KCs). The induction of PCD, the interplay between different forms of PCD, and the potential harm or benefit of PCD in liver fibrosis are topics of ongoing research. Evidences suggest that PCD is a complex process with dual effects on liver fibrosis. The purpose of this review is to summarize the most recent advances in PCD and liver fibrosis research.

Keywords:

• liver fibrosis
• necroptosis
• pyroptosis
• ferroptosis
• autophagy
• apoptosis

Abbreviations

PCD, programmed of cell death; HSCs, hepatic stellate cells; ECM, extracellular matrix; LSECs, hepatic sinusoid endothelial cells; KCs, kupper cells; HCC, hepatocellular carcinoma; EMT, epithelial-mesenchymal transition; DAMPs, damaged-associated molecular patterns; PBC, primary biliary cholangitis; HBV, hepatitis B virus; TNF, tumor necrosis factor; TNFR, tumor necrosis factor receptor; TRADD, TNF-associated death domain; TRAF2, TNFR-associated factor 2; RIPK, receptor-interacting serine-threonine kinase; CIAP1/2, cellular inhibitor of apoptosis 1/2; LUBAC, linear ubiquitin chain assembly complex; TLR, toll-like receptor; TRIF, domain-containing adapter-inducing interferon-β; MLKL, mixed lineage; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ALD, alcoholic fatty liver disease; HMGB1, high mobility group 1; PAMPs, pathogen-associated molecular patterns; TLR4, toll-like receptor 4; NLRP3, nod-, lrp-, and pyrin domain-comtaning 3; ɑ-SMA, alpha smooth muscle actin; MMP2, matrix metalloproteinase 2; MMP9, matrix metalloproteinase 9; NF-κB, nuclear factor kappa-beta; ASC, apoptosis-associated speck-like protein containing a CARD; GSDMD, gasdermin-D; IRAK1, IL-1 receptor associated kinase 1; TAK1, TGF-β-activated kinase 1; IκB, inhibitor of NF-κB; TFRC, transferrin receptor; STEAP3, six-transmembrane epithelial antigen of prostate 3; ALRP, AIM2-like receptor protein; NOX2, nicotinamide adenine dinucleotide phosphate oxidase; ATGs, autophagy-related proteins; GPXs, cystine-glutamate antiporter system Xc- and glutathione peroxidases; SLC11A2, solute carrier family 11 member 2; NCOA4, cargo receptor nuclear receptor coactivator 4; SLC40A1, solute carrier family 40 member 1; GPX4, glutathione peroxidase 4; Hsp70, heat shock protein 70; BH3-only proteins, BCL-2 homology domain 3 only proteins; MOMP, mitochondrial outer membrane permeabilization; APF-1, apoptotic peptidase activating factor 1; FASL, FAS ligand; FADD, FAS associated via death domain; SIRPα, signal regulatory protein ɑ; NK cells, natural killer cells; NKT cells, natural killer T cells; ROS, reactive oxygen species; GSH, glutathione; BM-MSCs, bone marrow derived mesenchymal stem cells; ATF3, activating transcription factor 3; hucMSC-ex, exosomes derived from human umbilical cord mesenchymal stem cells; CD8⁺ Trm, CD8⁺ tissue-resident memory T cells; EGR1, early growth response 1; YAP, yes-associated protein.

Additional Information

Correspondence and requests for materials should be addressed to the corresponding author.

Data Sharing Statement

All data generated or analyzed during this study are included in this published article.

Disclosure

The authors declare that they have no conflicts of interest.