Mitochondrial-mediated nuclear remodeling and macrophage polarizations: A key switch from liver fibrosis to HCC progression

• Published in: Experimental cell research 2024-01, Vol.434 (1), p.113878-113878, Article 113878
• Main Authors: Verma, Shobhit, Ishteyaque, Sharmeen, Washimkar, Kaveri R, Verma, Smriti, Nilakanth Mugale, Madhav
• Format: Article
• Language: English
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2023.113878

Liver fibrosis is a significant health burden worldwide and has emerged as the leading cause of Hepatocellular carcinoma (HCC) incidence. Mitochondria are the dynamic organelles that regulate the differentiation, survival, and polarization of macrophages. Nuclear-DNA-associated proteins, micro-RNAs, as well as macrophage polarization are essential for maintaining intracellular and extra-cellular homeostasis in the liver parenchyma. Dysregulated mitochondrial coding genes (ETS complexes I, II, III, IV, and V), non-coding RNAs (mitomiRs), and nuclear alteration lead to the production of reactive oxygen species (ROS) and inflammation which are implicated in the transition of liver fibrosis into HCC. Recent findings indicated the protecting effect of E74-like factor 3/peroxisome proliferator-activated receptor-γ (Elf-3/PPAR-γ). HDAR-y inhibits the deacetylation of PPAR-y and maintains the PPAR-y pathway. Elf-3 plays a tumor suppressive role through epithelial-mesenchymal transition-related gene and zinc finger E-box binding homeobox 2 (ZEB-2) domain. Additionally, the development of HCC includes the PI3K/Akt/mTOR and transforming Growth Factor β (TGF-β) pathway that promotes the Epithelial-mesenchymal transition (EMT) through Smad/Snail/Slug signaling cascade. In contrast, the TLR2/NOX2/autophagy axis promotes M2 polarization in HCC. Thus, a thorough understanding of the mitochondrial and nuclear reciprocal relationship related to macrophage polarization could provide new research opportunities concerning diseases with a significant impact on liver parenchyma towards developing liver fibrosis or liver cancer. Moreover, this knowledge can be used to develop new therapeutic strategies to treat liver diseases.