Drugging the efferocytosis process for treating hepatic fibrosis: dual roles, mechanisms, and therapeutics

The removal of apoptotic cells by phagocytes, called 'efferocytosis', is vital for preserving tissue homeostasis. Faulty efferocytosis contributes to a rising list of chronic inflammatory diseases, including liver fibrosis (LF). A major characteristic of LF is ongoing, unresolved inflammation, usually linked to an overactive immune response, oxidative stress, imbalances between proteases and antiproteases, and heightened cell death. This process activates hepatic stellate cells, resulting in an overaccumulation of extracellular matrix. Although excessive cell death in LF is well documented, new findings emphasize issues in the following clearance process, called efferocytosis. Thus far, studies have indicated that upon LF, liver-resident Kupffer cells and macrophages from infiltrating monocytes are involved in clearing apoptotic cells, limiting inflammation, and repairing damage. Efferocytosis facilitates LF in rare situations, including the prolonged release of transforming growth factor-beta during continuous injury repair and the accumulation of uncleared ACs that emit damage-associated molecular patterns, which may result in sustained activation. This process leads to ongoing inflammation and ECM buildup. Our knowledge of how liver macrophages execute efferocytosis and malfunctions in LF is still incomplete. In this review, we critically analyse the study and highlight the significant duality of efferocytosis in the pathogenesis of LF. Herein, we suggest future paths for fundamental and clinical research in LF, emphasizing new treatment possibilities that focus on the root causes of the disease instead of just alleviating symptoms.