Observational studies and clinical trials suggest associations between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, the causal relationships between these factors and hepatic cancer remain to be established. To explore the causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. This study employed comprehensive two-sample Mendelian randomization (MR) utilizing publicly available genetic data (GWAS) to analyze causal relationships between 731 immune cell traits, 91 inflammatory factors, 1400 serum metabolites, and hepatic cancer. The primary analysis used inverse variance-weighted (IVW) MR, with additional sensitivity tests to assess the validity of causal relationships. After correction for heterogeneity and horizontal pleiotropy, in exploring the causal relationships between immune cell groups and hepatic cancer, we found that Terminally Differentiated CD4⁻CD8⁻ T cell %T cell was negatively associated with hepatic cancer, serving as a protective factor, while Effector Memory CD4⁻CD8⁻ T cell %CD4⁻CD8⁻ T cell was positively associated with hepatic cancer, acting as a risk factor. In investigating the causal relationships between inflammatory factors and hepatic cancer, C–C motif chemokine 19 levels were positively associated with hepatic cancer, representing a risk factor, while Interleukin-10 levels were negatively associated with hepatic cancer, acting as a protective factor. Regarding the causal relationships between serum metabolites and hepatic cancer, (N(1) + N(8))-acetylspermidine levels were negatively associated with hepatic cancer, serving as a protective factor, while 1-(1-enyl-palmitoyl)-GPC (p-16:0) levels were positively associated with hepatic cancer, acting as a risk factor. Our MR analysis indicates causal relationships between immune cells, inflammatory factors, serum metabolites, and hepatic cancer. However, further validation is needed to assess the potential of these immune cells, inflammatory factors, and serum metabolites as preventive or therapeutic targets for hepatic cancer.

Mitochondria play a multifaceted role in tumorigenesis, influencing energy metabolism, redox balance, and apoptosis. However, whether mitochondrial traits causally affect cancer risk remains unclear. This study aimed to evaluate the potential causal effects of 82 mitochondrial-related exposures on six major cancers—hepatic, colorectal, lung, esophageal, thyroid, and breast—using Mendelian randomization (MR). Two-sample MR analysis was performed using the inverse variance weighted (IVW) method, with MR-Egger regression and weighted median as complementary approaches. Sensitivity analyses (Cochran’s Q test, MR-Egger intercept, leave-one-out) and the Steiger test were applied to assess heterogeneity, pleiotropy, and causal directionality. We observed a negative correlation between “39S ribosomal protein L34, mitochondrial”, and others, with hepatic cancer, while “[Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 2, mitochondrial”, and others exhibited a positive correlation with hepatic cancer. “Phenylalanine-tRNA ligase, mitochondrial”, and others demonstrated a negative association with colorectal cancer, whereas “Methylmalonyl-CoA epimerase, mitochondrial”, and others exhibited a positive correlation with colorectal cancer. “Succinate dehydrogenase assembly factor 2, mitochondrial” exhibited a negative correlation with lung cancer, while “Superoxide dismutase [Mn], mitochondrial levels” showed a positive correlation with lung cancer. “Lon protease homolog, mitochondrial” demonstrated a positive correlation with esophageal cancer. “Iron-sulfur cluster assembly enzyme ISCU, mitochondrial”, and others exhibited a negative correlation with thyroid cancer, while “Diablo homolog, mitochondrial”, and others showed a positive correlation with thyroid cancer. “ADP-ribose pyrophosphatase, mitochondrial”, and others exhibited a negative correlation with breast cancer, while “39S ribosomal protein L34, mitochondrial”, and others showed a positive correlation with breast cancer. This study provides MR-based evidence that specific mitochondrial-related traits have causal effects on the risk of several common cancers. Notably, certain single-nucleotide polymorphisms (SNPs) acted as instrumental variables across multiple cancer types through shared mitochondrial mechanisms, such as oxidative stress regulation and metabolic reprogramming. These findings highlight mitochondria as cross-cutting contributors to cancer susceptibility and suggest potential avenues for mitochondrial-targeted prevention and therapy. The identification of pleiotropic genetic variants also offers insights for developing shared biomarkers and therapeutic targets across malignancies.

Objective: This study aimed to screen and identify central genes associated with the progression of non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC), to establish prognostic and clinical prediction models based on the expression of these genes, and to evaluate the intervention of a traditional Chinese medicine (TCM) formula—SPXJF—on the development of NAFLD into HCC through network pharmacology analysis and in vitro and in vivo validation. Methods: Datasets for analysis were retrieved from multiple public databases using bioinformatics techniques. Through network pharmacology analysis, SPXJF's active components and their related targets were assessed, while in vitro experiments validated the inhibitory effects of SPXJF on the growth and migration of HepG2 cells. Results: The results revealed that the expression levels of the two central genes, regulator of cell cycle gene (RGCC) and atypical chemokine receptor 3 (ACKR3), were closely tied to the survival prognosis of HCC patients. Furthermore, SPXJF significantly inhibited the proliferation and migration of HepG2 cells. Conclusion: RGCC and ACKR3, as hub genes, significantly influence HCC patient survival during “NAFLD-HCC” progression. The risk scoring system and prediction model perform well. In vitro experiments showed that SPXJF could inhibit the proliferation and invasion of hepG2 cells. These findings support the discovery of molecular targets for early diagnosis and drug intervention in HCC. They also underscore TCM's potential in anti-HCC strategies and clinical application.

Primary hepatocellular carcinoma (HCC), a leading variant of primary liver cancer, holds significant global prevalence with strong implications for morbidity, mortality, and prognosis. Prevention and treatment paradigms are perpetually evolving in response to this malignancy. Ferroptosis, an iron and reactive oxygen species (ROS) dependant mode of cellular death, is catalyzed by an overabundance of lipid peroxidation, subsequently causing plasma membrane rupture. There is a unique interest in the relationship of ferroptosis with HCC development and progression, as compared to the interplay of apoptosis, autophagy, and necroptosis. Recent discoveries underscore the implications of ferroptosis in HCC evolution. Moreover, Traditional Chinese Medicine (TCM) and its respective active components display anti-HCC properties, a mechanism thought to be primarily attributed to the induction of ferroptosis in HCC cells. In support of preventive and therapeutic strategies for HCC, this manuscript provides a comprehensive review of the role of ferroptosis in HCC, its regulatory network, and the cutting-edge research focused on the treatment of HCC via ferroptosis modulation using TCM.