Immunoglobulin κ drives liver regeneration by stabilizing MYLK to maintain cytoskeletal integrity and promote hepatocyte proliferation

Background and Objectives Liver regeneration necessitates coordinated cytoskeletal dynamics, yet the key molecular orchestrators remain incompletely defined. Intriguingly, recent studies reveal a novel role for hepatocyte-derived Igκ in promoting hepatocyte survival during liver injury. However, the precise mechanisms by which immunoglobulin κ (Igκ) governs liver regeneration and its potential as a central coordinator remain elusive. This study aims to elucidate the role of Igκ in liver regeneration following injury and to define the underlying molecular mechanisms. Methods Igκ expression was assessed in liver biopsies from patients with drug-induced liver injury (DILI) using immunohistochemistry. To investigate its role in regeneration, hepatocyte-specific Igκ-knockout mice were subjected to partial hepatectomy (PHx) or acetaminophen (APAP)-induced acute liver injury. Functional and mechanistic studies were performed in the normal human hepatocyte cell line THLE-2 through Igκ knockdown or overexpression, combined with multi-omics profiling, immunoprecipitation, and mass spectrometry. The therapeutic potential of Igκ was validated by AAV8-mediated hepatic delivery of Igκ in knockout mice. Results Igκ expression is significantly upregulated in both human DILI patients and murine injury models upon hepatic damage. Hepatocyte-specific Igκ deletion impaired liver regeneration, characterized by disrupted cytoskeletal organization and diminished hepatocyte proliferation. Mechanistically, Igκ directly binds to myosin light chain kinase (MYLK), shielding it from K48-linked ubiquitination and proteasomal degradation, thereby preserving cytoskeletal integrity and facilitating Yes-associated protein (YAP) nuclear translocation to activate proliferative pathways. Crucially, AAV8-mediated hepatic Igκ delivery in knockout mice rescues MYLK protein levels, restores cytoskeletal integrity, and promotes liver regeneration. Conclusions Our study identifies Igκ as a pivotal regulator of liver regeneration by stabilizing MYLK to maintain cytoskeletal dynamics and potentiate YAP-dependent proliferative signaling, thereby proposing a potential therapeutic strategy for enhancing hepatic repair.