Pyroptosis in Hepatocellular Carcinoma: A Retrospective Analysis

   

Houhong Wang^*

Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, China

*Corresponding Author: Houhong Wang, Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, China

Citation: Wang H. Pyroptosis in Hepatocellular Carcinoma: A Retrospective Analysis. J Can Ther Res. 5(1):1-5.

Received: April 05, 2025 | Published: October 14, 2025
 
Copyright© 2025 Genesis Pub by Wang H. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC BY 4.0). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are properly credited. 

DOI:  https://doi.org/10.52793/JCTR.2025.5(1)-48

Abstract

Hepatocellular carcinoma (HCC) is characterized by dysregulated cell death pathways, with pyroptosis emerging as a critical modulator of tumor inflammation and immune surveillance. Pyroptosis, a pro-inflammatory programmed cell death mediated by gasdermin D (GSDMD) pores, is governed by NLRP3 inflammasome activation and caspase- 1/4/5 signaling. This retrospective analysis synthesizes evidence from 38 recent studies (PubMed, 2020–2025) to dissect the role of pyroptosis in HCC pathogenesis, diagnosis, and therapy. Key findings include dysregulation of pyroptosis-related genes (NLRP3, GSDMD, CASP1) associated with tumor progression, immune microenvironment remodeling, and treatment response. Clinically, pyroptosis signatures predict prognosis and inform precision therapies, with inflammasome inhibitors and pyroptosis inducers showing promise in preclinical models. This review highlights the translational potential of pyroptosis research for enhancing HCC management through inflammatory pathway targeting.

Keywords

Hepatocellular carcinoma; Iron metabolism genes; Antioxidant System Genes; Molecular mechanisms; Oncogenic signaling crosstalk; T Cell.

Introduction

HCC, the most common primary liver cancer, has a dismal prognosis due to aggressive progression and immune evasion. Pyroptosis, identified as a distinct cell death modality in 2015, is characterized by plasma membrane pore formation, cytokine release (IL-1β, IL-18), and sterile inflammation. Key components include nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, caspase-1/4/5, and gasdermin D (GSDMD). Dysregulation of pyroptosis in HCC has been linked to hepatitis virus infection, metabolic stress, and tumor-associated macrophage polarization, making it a pivotal target for immune-oncological interventions.

Methods

Literature search

A systematic PubMed search was performed using keywords: ("hepatocellular carcinoma" OR "HCC") AND ("pyroptosis" OR "inflammasome" OR "gasdermin D" OR "caspase-1"). Inclusion criteria: English studies (2020–2025) reporting pyroptosis-related mechanisms, gene expression, or clinical outcomes in HCC. Exclusion criteria: reviews, non-clinical studies, or non-HCC cancer types.

Data synthesis

Studies were categorized by molecular pathways (inflammasome activation, GSDMD processing, cytokine secretion), clinical relevance (diagnosis, prognosis), and therapeutic interventions. Quantitative data (gene expression levels, survival statistics, treatment efficacy) were extracted and tabulated.

Results

Pyroptosis-related gene dysregulation in HCC

1. Inflammasome components

• NLRP3: Overexpressed in 68% of HCC tissues (mRNA: 2.15 ± 0.78 vs. normal liver 1.00 ± 0.19, p<0.001, Table 1), correlated with IL-1β secretion and macrophage recruitment.
• CASP1: Activated caspase-1 protein levels increased 1.8-fold in HCC, promoting GSDMD cleavage and pore formation [1].

 

2. Gasdermin family

• GSDMD: Full-length GSDMD (55 kDa) reduced in advanced HCC, while cleaved GSDMD-NT (30 kDa) increased in tumor margins, indicating active pyroptosis (Western blot intensity: 0.65 ± 0.21 vs. 1.23 ± 0.35 in normal, p=0.008, [2]).
• GSDME: Downregulated in 55% of HCC, correlating with reduced pyroptosis and increased chemoresistance (OR=2.5, 95% CI: 1.3–4.8, p=0.012, [3]).

 

Gene	HCC (n=200)	Normal Liver (n=50)	Fold Change	p-value
NLRP3	2.15 ± 0.78	1.00 ± 0.19	2.15x	<0.001
CASP1	1.72 ± 0.65	1.00 ± 0.22	1.72x	0.003
GSDMD	0.89 ± 0.31	1.00 ± 0.15	0.89x	0.045
GSDME	0.68 ± 0.25	1.00 ± 0.20	0.68x	0.008
Note: Data shown as mean ± SD (qRT- PCR/Western blot); fold change relative to normal liver.

Table 1: Key Pyroptosis Gene Expression in HCC Tissues. 

Molecular mechanisms of pyroptosis in HCC

1. Inflammasome activation pathways

• Oxidative Stress: Hepatitis B virus (HBV) X protein induces NLRP3 inflammasome activation via reactive oxygen species (ROS) generation, promoting IL-18 secretion and tumor angiogenesis (Figure 1),[4]).
• Metabolic Dysfunction: Steatotic HCC cells activate NLRP3 through mitochondrial damage-associated molecular patterns (mtDAMPs), enhancing pyroptosis in tumor stroma (GSEA NES=2.3, p<0.01, [5]).

 

2. Immune microenvironment interaction

• Macrophage Polarization: Pyroptotic HCC cells release HMGB1 and ATP, recruiting M1-like macrophages (CD86⁺, iNOS⁺) and activating dendritic cells (DCs), enhancing anti-tumor immunity (Table 2, [6]).
• T Cell Regulation: IL-1β/IL-18 secretion promotes Th17 cell differentiation, while excessive pyroptosis induces T cell exhaustion via PD-L1 upregulation (PD-L1+ T cells: 30% vs. 10% in non-pyroptotic tumors, p<0.01, [7]).

 

Cell Type	Stimulus	Functional Impact
M1 Macrophages	GSDMD-NT pores, IL- 1β	Tumor cell phagocytosis, IFN-γ secretion
Dendritic Cells	ATP/P2X7R signaling	MHC class I upregulation, T cell priming
Tregs	Excessive IL-1β	FoxP3+ T cell expansion, immune suppression

Figure 2: Immune microenvironment interaction.

Clinical Relevance of Pyroptosis Signatures

1. Diagnostic and prognostic biomarkers

• Pyroptosis Score (PS): A 4-gene panel (NLRP3, CASP1, GSDMD, GSDME) achieves AUC-ROC=0.89 for distinguishing HCC from cirrhosis (n=300, p<0.001,) (Table 3).
• Prognosis: High PS predicts better overall survival (median OS: 28 vs. 16 months, HR=0.6, 95% CI: 0.4– 0.9, p=0.015), [2]), while NLRP3 overexpression correlates with vascular invasion (OR=3.2, 95% CI: 1.8–5.6, p<0.001).

 

2. Therapeutic interventions 

Inflammasome inhibitors

• MCC950: Blocks NLRP3 inflammasome, reducing IL-1β secretion and tumor growth (tumor volume: 0.6± 0.1 cm³ vs. control 1.2 ± 0.2 cm³, p=0.005, Table 4, [8]).
• CRID3: Inhibits caspase-1, decreasing GSDMD cleavage and promoting HCC cell survival (IC50 increase: 2-fold in CRID3-treated cells, p<0.01, [9]).