CiR-EIS alleviates metabolic dysfunction-associated steatohepatitis by modulating macrophage polarization involving...

Metabolic dysfunction-associated steatohepatitis (MASH) is a significant public health concern, with macrophage phenotypes implicated in its progression. Although extensive inflammation-suppressing circular RNA (ciR-EIS, formerly named as hsa_circ_0008882) has been implicated in inflammation regulation, its role in macrophage polarization within the context of MASH remains unexplored. This study aimed to clarify the effect of ciR-EIS on macrophage polarization in MASH.

Immunofluorescence-fluorescence in situ hybridization was used to evaluate the localization of ciR-EIS in human liver sections. THP-1-derived macrophages (TDMs) were utilized to study ciR-EIS functions in vitro. Flow cytometry and RT-qPCR were employed to evaluate macrophage polarization after transfection. Bodipy assay was used to measure lipid buildup in HepG2 cells. Immunohistochemistry was used to confirm liver insulin-like growth factor 1 (IGF1) expression. Retrospective clinical records were analyzed to examine the association between cir-EIS, IGF1, and MASH.

CiR-EIS was downregulated in patients with MASH and colocalized with the macrophage marker CD68. CiR-EIS and mitochondrially encoded NADH dehydrogenase 5 (MT-ND5) were downregulated in M1 macrophages and upregulated in M2 macrophages. TDM-derived supernatants overexpressed ciR-EIS, significantly reducing HepG2 lipid deposition and inhibiting LX2 proliferation. Overexpression of ciR-EIS in TDMs significantly inhibited M1 macrophage markers CD86, interleukin-1 beta, and tumor necrosis factor-alpha while enhancing M2 macrophage markers CD163 and CD206. CiR-EIS regulated macrophage polarization in a manner involving the miR-548m/IGF1 axis. Serum IGF1 levels were positively correlated with ciR-EIS, and both of them were notably reduced in patients with MASH and inversely correlated with APRI and FIB-4 scores.

CiR-EIS regulates macrophage polarization in a manner involving the miR-548/IGF1 axis, thereby reducing hepatocyte lipid accumulation and stellate cell proliferation in MASH. It demonstrates potential as a diagnostic marker and therapeutic target for MASH.