Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH

International Journal of Molecular Sciences · 9 authors, 6 centres

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This preclinical study investigated cilostazol's effects on non-alcoholic steatohepatitis (NASH) using the STAM™ mouse model.

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This preclinical study investigated cilostazol's effects on non-alcoholic steatohepatitis (NASH) using the STAM™ mouse model. The authors demonstrated that cilostazol treatment ameliorated ballooning degeneration and inflammation in NASH livers, but did not improve lipid or glucose profiles. Validation using Gene Expression Omnibus datasets from human, rat, and mouse NASH livers showed upregulation of genes related to iron metabolism and ferroptosis. A key limitation is the reliance on a specific animal model; the findings require further research to understand cilostazol's long-term effects and applicability in a clinical context.

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preclinical research

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ORIGINAL PAPER

PMC10454295

Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH

International Journal of Molecular Sciences

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ABSTRACT

Abstract Hepatic iron overload (HIO) is a hallmark of nonalcoholic fatty liver disease (NAFLD) with a poor prognosis. Recently, the role of hepatic erythrophagocytosis in NAFLD is emerging as a cause of HIO. We undertook various assays using human NAFLD patient pathology samples and an in vivo nonalcoholic steatohepatitis (NASH) mouse model named STAM TM . To make the in vitro conditions comparable to those of the in vivo NASH model, red blood cells (RBCs) and platelets were suspended and subjected to metabolic and inflammatory stresses. An insert-coculture system, in which activated THP-1 cells and RBCs are separated from HepG2 cells by a porous membrane, was also employed. Through various analyses in this study, the effect of cilostazol was examined. The NAFLD activity score, including steatosis, ballooning degeneration, inflammation, and fibrosis, was increased in STAM TM mice. Importantly, hemolysis occurred in the serum of STAM TM mice. Although cilostazol did not improve lipid or glucose profiles, it ameliorated hepatic steatosis and inflammation in STAM TM mice. Platelets (PLTs) played an important role in increasing erythrophagocytosis in the NASH liver. Upregulated erythrophagocytosis drives cells into ferroptosis, resulting in liver cell death. Cilostazol inhibited the augmentation of PLT and RBC accumulation. Cilostazol prevented the PLT-induced increase in ectopic erythrophagocytosis in in vivo and in vitro NASH models. Cilostazol attenuated ferroptosis of hepatocytes and phagocytosis of RBCs by THP-1 cells. Augmentation of hepatic erythrophagocytosis by activated platelets in NASH exacerbates HIO. Cilostazol prevents ectopic erythrophagocytosis, mitigating HIO-mediated ferroptosis in NASH models. Keywords: NASH, cilostazol, hepatic iron overload, ferroptosis, erythrophagocytosis

CITATION EXPORT

Joon Beom Park, Kangeun Ko, Yang Hyun Baek et al.. Pharmacological Prevention of Ectopic Erythrophagocytosis by Cilostazol Mitigates Ferroptosis in NASH. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms241612862

AUTHORS

9 · 6 CENTRES

Joon Beom Park, Kangeun Ko, Yang Hyun Baek, Woo Young Kwon, Sunghwan Suh, Song-Hee Han, Yun Hak Kim, Hye Young Kim, Young Hyun Yoo

1Department of Anatomy and Cell Biology, Dong-A University College of Medicine, Busan 49201, Republic of Korea; [email protected] (J.B.P.); [email protected] (K.K.); [email protected] (W.Y.K.)
2Department of Gastroenterology, Dong-A University College of Medicine, Busan 49201, Republic of Korea; [email protected]
3Department of Endocrinology, Dong-A University College of Medicine, Busan 49201, Republic of Korea; [email protected]
4Department of Pathology, Dong-A University College of Medicine, Busan 49201, Republic of Korea; [email protected]
5Department of Anatomy, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea; [email protected]
6Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea