Plant-Derived miR-55 Alleviates Liver Fibrosis by Disrupting the CK2α/SMO Complex and Promoting SMO Ubiquitination

TL;DR

A plant-based miRNA called miR-55, delivered orally, reduces liver fibrosis by disrupting a protein complex and promoting degradation of a key signaling protein.

Contribution

miR-55 is shown to alleviate liver fibrosis via a novel mechanism involving disruption of the CK2α/SMO complex and SMO ubiquitination.

Findings

Oral delivery of miR-55 improved liver injury, lipid dysregulation, and collagen deposition in a rat model.

miR-55 disrupts the CK2α/SMO complex, leading to SMO ubiquitination and degradation, and inhibits the Gli1 pathway.

miR-55 downregulates fibrogenic and pro-inflammatory genes, achieving effects comparable to a traditional herbal decoction.

Abstract

The development of RNA-based drugs for MAFLD-related fibrosis is severely hampered by the poor oral bioavailability of nucleic acids. This study employed a novel, patent-protected LNP formulation to orally deliver plant-derived miR-55 and investigate its therapeutic potential, focusing on its novel mechanism of action via the CK2α/SMO interaction. In a rat model established with a methionine-choline-deficient diet, orally administered miR-55 markedly improved liver injury, lipid dysregulation, oxidative stress, and pathological collagen deposition. The anti-fibrotic efficacy was quantitatively confirmed by a significant reduction in hepatic hydroxyproline content and downregulation of key fibrogenic genes (Col1a1, Col3a1, TIMP-1, TGF-β1, CTGF) and pro-inflammatory cytokines (TNF-α, IL-6), achieving effects comparable to the full Ge Xia Zhu Yu Decoction. Mechanistically, both bioinformatic prediction and in vivo validation indicated that miR-55 is predicted to target CK2α. This targeting suppressed CK2α expression and disrupted the endogenous CK2α-SMO complex, thereby promoting the ubiquitin-mediated degradation of SMO—a previously unreported mechanism. This cascade inhibited the downstream Gli1 pathway and downregulated pro-fibrotic and pro-angiogenic factors (VEGF, PDGF), thereby providing a comprehensive mechanistic basis for the therapeutic effects. This study is the first to provide evidence that orally delivered, plant-derived miR-55 may act as a natural modulator that potentially through disrupting the CK2α/SMO interaction via a unique complex disruption-promoted degradation mechanism, attenuating Hedgehog signaling and alleviating liver fibrosis. These findings offer important insights into cross-kingdom regulation and highlight miR-55 as a potential targeted therapeutic candidate.

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