The pathogenesis of organ fibrosis: Focus on necroptosis

Abstract

Fibrosis is a common process of tissue repair response to multiple injuries in all chronic progressive diseases, which features with excessive deposition of extracellular matrix. Fibrosis can occur in all organs and tends to be nonreversible with the progress of the disease. Different cells types in different organs are involved in the occurrence and development of fibrosis, that is, hepatic stellate cells, pancreatic stellate cells, fibroblasts and myofibroblasts. Various types of programmed cell death, including apoptosis, autophagy, ferroptosis and necroptosis, are closely related to organ fibrosis. Among these programmed cell death types, necroptosis, an emerging regulated cell death type, is regarded as a huge potential target to ameliorate organ fibrosis. In this review, we summarize the role of necroptosis signalling in organ fibrosis and collate the small molecule compounds targeting necroptosis. In addition, we discuss the potential challenges, opportunities and open questions in using necroptosis signalling as a potential target for antifibrotic therapies.

Liposome-Based Silibinin for Mitigating Nonalcoholic Fatty Liver Disease: Dual Effects via Parenteral and Intestinal Routes

“…As a passive targeting organ, oral drugs absorbed into the blood will first gather in the liver, meaning that the liver content of Sil is bound to increase . For some agents, such as berberine, resveratrol, and curcumin, increase in their oral bioavailability and liver concentrations can effectively enhance their pharmacological activities (e.g., anti-NAFLD and antiliver fibrosis), , which is more necessary for liver fibrosis as fibrous barriers will further prevent efficacious drugs from entering the liver. , More elaborate modifications for Sil-Lip, such as galactosylated Sil-Lip, will achieve accurate active targeting and be more effective for targeted delivery of Sil to hepatocytes, which warrants further investigation …”

Therapeutic targets of fibrosis: Translational advances and current challenges

“…An accompanying review by Hao et al (2023) similarly addresses fibrosis across multiple organs, drilling down on the role of necroptosis involved in fibrosis deposition, and the available small‐molecule compounds that can target this form of programmed cell death. Caspase 8 is described as a key switch between apoptosis and necroptosis, due to the cleaving capacity of caspase 8.…”

“…As illustrated in their fig. 3, when caspase 8 is inhibited, active RIPK1 is available to interact with RIPK3 to cause its phosphorylation, thereby activating MLKL and forming the necrosome complex (Hao et al, 2023). This action can trigger increased cell membrane permeability, cytoplasm and organelles swelling and overflow of cell components into the microenvironment (Galluzzi et al, 2017), with subsequent necroptotic cell death.…”

“…This review discusses the core components of necroptosis, the activation of the signalling pathway and the role that necroptosis plays in tissue fibrosis, focussing on stellate cells, macrophages, neutrophils and fibroblasts, and then various disease settings including cardiac fibrosis, liver fibrosis, kidney fibrosis, pulmonary fibrosis and pancreatitis fibrosis. The authors also consider the therapeutic potential of targeting necroptosis in fibrosis of various organs, including the use of inhibitors of RIPK1, RIPK3 and MLKL (Hao et al, 2023).…”

“…As illustrated in their fig. 3, when caspase 8 is inhibited, active RIPK1 is available to interact with RIPK3 to cause its phosphorylation, thereby activating MLKL and forming the necrosome complex (Hao et al, 2023).…”