PANoptosis in hepatocellular carcinoma: Underlying mechanisms

Abstract

PANoptosis is an inflammatory programmed cell death pathway possessing critical characteristics of apoptosis, pyroptosis, and necroptosis. It is regulated by PANoptosome complexes, involves interaction between these three key programmed cell death pathways, yet is distinct from any alone. PANoptosis holds vital significance in liver-related diseases, particularly hepatocellular carcinoma (HCC). This article summarizes research on the mechanism and treatments of PANoptosis in HCC. Current research has partially elucidated PANoptosis-related mechanisms in HCC and identified several molecules modulating it. Therapeutic strategies targeting PANoptosis hold significant promise. Investigations into these critical molecules have led to the development of traditional targeted drug therapies and emerging strategies like nanotechnology-based immunocombination therapies. However, there are still challenges in the mechanistic and pharmacological studies of PANoptosis in HCC, including the bidirectional regulation of key apoptotic factors, specific molecular mechanisms, and preclinical models. This article offers a new orientation for studying the pathogenesis and potential therapeutic strategies for HCC.

Keywords: Hepatocellular carcinoma; Mechanisms; PANoptosis; Programmed cell death; Treatment strategies.

Figure 1

Molecular mechanisms of pyroptosis, necroptosis, and apoptosis. ASC: Apoptosis-associated speck-like protein containing a CARD; BAX: Bcl-2 associated X protein; DD: Death domain; FADD: Fas-associated protein with death domain; GSDMD: Gasdermin D; N-GSDMD: N-terminal fragment of gasdermin D; MLKL: Mixed lineage kinase domain like pseudokinase; NEK7: Never in mitosis gene A-related kinase 7; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NLR family pyrin domain containing 3; PAMPs: Pathogen-associated molecular patterns; RIPK1: Receptor-interacting serine/threonine kinase 1; RIPK3: Receptor interacting serine/threonine kinase 3; ROS: Reactive oxygen species; TLR: Toll-like receptor; TNF-α: Tumor necrosis factor-alpha; TRADD: Tumor necrosis factor receptor-associated death domain protein.

Figure 2

Role of PANoptosis in hepatocellular carcinoma. Mechanisms of PANoptosis in hepatocellular carcinoma. Factors that inhibit the hepatocellular carcinoma (HCC) process are covered in green, like hepatitis B virus X (HBx) protein. Factors that can promote the HCC process are covered in red. Triple motif protein 21 (TRIM21) and caspase-8 exhibit both positive and negative regulatory mechanisms in HCC. Through positive regulation, TRIM21 can inhibit tumor suppression by inhibiting the p62 sequestosome 1-kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2 (p62-Keap1-Nrf2) antioxidant pathway. In contrast, its negative regulation involves two inhibitory pathways, receptor-interacting serine/threonine kinase 1 and vacuolar protein sorting 72 (VPS72), which suppress HCC progression. Caspase-8, while enhancing the tumor-suppressive activity of caspase-3, can also promote HCC development through interactions with Fas-associated protein with death domain (FADD) and receptor-interacting serine/threonine kinase 1 (RIPK1). AIM2: Absent in melanoma 2; NLRP3: NLR family pyrin domain containing 3; ZBP1: Z-DNA binding protein 1.