Sustained Hydrogel Delivery of G-CSF Ameliorates Alcoholic Liver Disease via HIF-1α-Mediated Suppression of Apoptosis and Inflammation

Alcoholic liver disease (ALD), a prevalent chronic liver disorder, has garnered global attention due to its significant health risks and limited treatment options. Recombinant granulocyte colony-stimulating factor (G-CSF), a drug with potent anti-inflammatory and antiapoptotic effects, shows limited utility in ALD therapy because of its short half-life. To address this limitation, we developed a hydrogel-encapsulated delivery system that prolongs G-CSF bioavailability, thereby enabling sustained suppression of cytokine release and apoptosis in ALD. The combination of recombinant G-CSF with carboxymethylcellulose sodium hydrogel (G-CSF&hydrogel) demonstrates excellent biocompatibility, controlled release, and favorable biosafety. G-CSF&hydrogel reduced alanine aminotransferase (ALT) levels from 190 IU/L to 70 IU/L and aspartate aminotransferase (AST) from 790 IU/L to 300 IU/L, compared with 110 IU/L and 460 IU/L for G-CSF alone, indicating enhanced therapeutic efficacy. RNA sequencing revealed that the enhanced inhibitory effects of G-CSF&hydrogel on ethanol (EtOH)-induced pathology in AML-12 hepatocytes were mediated via the HIF-1α signaling pathway. This study presents an effective strategy for developing advanced hydrogel-based drug delivery systems targeting inflammatory liver conditions.