Hepatic Stellate Cell-Targeted Delivery of Ferroptosis Modulators for Liver Fibrosis: Emerging Nanocarriers, Pharmacological Targets and Translational Challenges
Author
Sakshi, Payal Kulpreet Kaur Sandhu, Sidhant Sharma, Dr. Avneet Gupta
Abstract
The frequent histological result of chronic hepatic damage is liver fibrosis, which is primarily caused by quiescent hepatic stellate cells (HSCs) being persistently activated into proliferative myofibroblasts that secrete extracellular matrix. Because selective induction of ferroptosis in activated HSCs reduces collagen deposition without necessarily harming hepatocytes, while hepatocyte or macrophage ferroptosis can worsen liver injury, ferroptosis—an iron-dependent form of regulated cell death characterised by unrestrained lipid peroxidation—has recently emerged as an appealing antifibrotic strategy. Because of this contradiction, the translation of ferroptosis-inducing pharmacology into safe antifibrotic therapy requires cell-selective administration.The system Xc−/glutathione/GPX4 axis, ACSL4-dependent lipid remodelling, iron-handling proteins, and the Nrf2-Keap1 and HIF-1α regulatory nodes are just a few examples of the molecular circuitry that connects ferroptosis to HSC biology. This review also examines the pharmacological agents—small molecules, natural products, and nucleic acid-based regulators—that take advantage of this circuitry. The growing toolkit of nanocarriers designed for HSC-selective delivery is then examined, including vitamin A/retinoid-decorated liposomes and lipid nanoparticles, polymeric and chitosan-based systems, peptide- and protein-guided platforms, inorganic and hybrid nanostructures, and exosome-based vehicles. It emphasises how ligand selection, particle architecture, and payload (small molecule, siRNA, or miRNA) determine antifibrotic efficacy and specificity.Lastly, the review critically examines translational barriers, such as the extracellular matrix and sinusoidal capillarization that prevent nanoparticle penetration, the possibility of unintentional hepatocellular ferroptosis, manufacturing and stability limitations, immunogenicity of carriers based on lipids and nucleic acids, and the lack of clinical trials and validated pharmacodynamic biomarkers. The key to moving HSC-targeted ferroptosis modulation from preclinical proof-of-concept to clinically feasible antifibrotic therapy is suggested to be bridging mechanistic pharmacology with logical nanocarrier engineering.
Keywords
Hepatic stellate cells; Ferroptosis; Liver fibrosis; Nanocarriers; Drug delivery; GPX4; SLC7A11; Vitamin A-targeted nanoparticles
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