Developing targeted therapeutic drugs for liver cancer remains a significant scientific and clinical challenge. Previous research by the authors showed that taraxasterol (TS) can enhance the antitumor immune response of T-lymphocytes, inhibiting the growth of liver cancer cells both in vivo and in vitro. To improve the targeting ability and efficacy of TS, the authors synthesized a novel compound, Bio-SS-TS, which utilizes the high expression of biotin receptors on tumor cell membranes to link biotin to TS for increased targeting to hepatocellular carcinoma cells, and its disulfide bond can be specifically hydrolyzed by high - level glutathione (GSH) in tumor cells to release the active component TS. In vitro, Bio-SS-TS reduced liver cancer cell (HepG2 and Huh7) proliferation, impaired mitochondrial membrane potential, decreased intracellular GSH content in tumor cells, increased the reactive oxygen species level, and promoted the release of cytochrome c. Endogenous GSH in cancer cells reduced the disulfide bond in Bio-SS-TS, releasing active TS components. In vivo, treatment with Bio-SS-TS caused no significant change in mouse body weight and no toxicity to the main organs. The present study comprehensively demonstrates that Bio-SS-TS exerts a potent anti - liver cancer effect by enhancing mitochondria-dependent apoptosis, which may provide a new candidate for targeted liver cancer therapy.

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients' quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum-CVE, Melissae extractum-ME, Taraxaci extractum-TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings.

Hepatocellular carcinoma (HCC) presents a formidable challenge in oncology, attributed to its association with chronic liver diseases and global prevalence. The immune microenvironment profoundly influences HCC progression, balancing immune suppression and antitumor responses. The Signal Transducer and Activator of Transcription 3 (STAT3) is central to this equilibrium, orchestrating immune dynamics and intertwining tumor progression with immune evasion mechanisms. Dysregulated STAT3 signaling, activated by various stimuli, including cytokines and growth factors, promotes an immunosuppressive milieu within HCC tumors, fostering tumor survival and proliferation while hindering immune surveillance. Non-coding RNAs and other molecules regulate this process, modulating STAT3 activity and influencing immune cell function. Moreover, therapeutic interventions targeting the STAT3 pathway, alongside advancements in radiotherapy, cancer vaccines, and diabetes-related drugs, offer promising strategies in HCC management. Integrating natural compounds with immunotherapy emerges as a novel approach, leveraging their ability to enhance antitumor immunity and counter immune evasion strategies. Understanding the multifaceted role of STAT3 and its interactions within the immune landscape of HCC is paramount for devising effective therapeutic interventions and improving patient outcomes.

Dandelion (Taraxacum genus), a perennial herb belonging to the Asteraceae family is widely distributed in hillside grasslands, roadsides, fields, and river beaches in middle and low-altitude areas. It has a long history of traditional Chinese medicine usage as a heat-clearing and detoxifying agent, often consumed as tea or vegetable. Multiple pharmacological studies have demonstrated the antiviral, antibacterial, anti-inflammatory, immune-regulating, antioxidant, anti-tumor, and other effects of the Taraxacum genus. Bioactive compounds associated with these effects include triterpenes and their saponins, phenolic acids, sterols and their glycosides, flavonoids, organic acids, volatile oils, and saccharides.

Acute liver failure is mainly caused by the overdose of acetaminophen (APAP) globally. The traditional Chinese medicinal (TCM) herb, Taraxacum, contains Taraxasterol (TAX) as one of the active components. It is a pentacyclic-triterpene compound isolated from this herb. Present work aimed to investigate the in vitro and in vivo protection effect of TAX in APAP-induced acute liver injury, and determine the potential regulatory mechamisms. The liver injury caused by APAP is attenuated by TAX, as shown by the alleviated pathological changes of mice liver and the reduced serological indexes. TAX evidently controlled the oxidative stress and liver inflammation in mice liver. In vitro studies found that TAX reversed the decrease in LO2 cell viability induced by APAP, and protected LO2 cells from APAP-induced injury. In addition, TAX reduced the secretion of inflammatory factors in RAW264.7 macrophages as induced via APAP. Besides, TAX inhibited oxidative stress in LO2 cells induced by APAP in vitro. Noteworthy, TAX enhanced protein and mRNA expressions of Nrf2 in vivo, and knockdown of Nrf2 by using adeno-associated virus (AAV)-Nrf2-KO attenuated inhibitory impact of TAX in acute liver injury induced by APAP. Also, AAV-NRF2-KO weakened the inhibitory impact of TAX against APAP-triggered liver inflammation and oxidative stress of mice liver. Moreover, TAX activated the Nrf2 signaling in APAP-induced LO2 cells, as shown by the increased nuclear Nrf2 expression together with downstream HO-1 expression in vitro. Inhibition of Nrf2 by using ML-385, anNrf2inhibitor, weakened the inhibitory effect of TAX against APAP-induced oxidative stress and cell injury in LO2 cells. Moreover, inhibition of Nrf2 attenuated anti-inflammatory effect of TAX for APAP-induced RAW264.7 cells. Collectively, TAX could protect against APAP-triggered hepatotoxicitythrough suppression of liver oxidative stress and inflammatory response in mice.

Taraxaci herba, as a traditional Chinese medicine, is the name of the Taraxacum genus in the Asteraceae family. Documented in the Tang Herbal Medicine (Tang Dynasty, AD 657-659), its medicinal properties cover a wide range of applications such as acute mastitis, lung abscess, conjunctival congestion, sore throat, damp-heat jaundice, and vision improvement. In the Chinese Pharmacopoeia (Edition 2020), more than 40 kinds of China-patented drugs containing Taraxaci herba were recorded. This review explores the evolving scientific understanding of Taraxaci herba, covering facets of ethnopharmacology, botany, phytochemistry, pharmacology, artificial cultivation, and quality control. In particular, the chemical constituents and pharmacological research are reviewed. Taraxaci herba has been certified as a traditional medicine plant, and its flavonoids, phenolic acids, and terpenoids have been identified and separated, which include Chicoric acid, taraxasterol, Taraxasteryl acetate, Chlorogenic acid, isorhamnetin, and luteolin; they are responsible for anti-inflammatory, antioxidant, antibacterial, anti-tumor, and anti-cancer activities. These findings validate the traditional uses of Taraxaci herba and lay the groundwork for further scientific exploration. The sources used in this study include Web of Science, Pubmed, the CNKI site, classic monographs, the Chinese Pharmacopoeia, the Chinese Medicine Dictionary, and doctoral and master's theses.

The field of personalized medicine has gained increasing attention in cancer care, with the aim of tailoring treatment strategies to individual patients for improved outcomes. Herbal medicine, with its long-standing historical use and extensive bioactive compounds, offers a rich source of potential treatments for various diseases, including cancer.

To provide an overview of the current knowledge and evidence associated with incorporating herbal compounds into precision medicine strategies for cancer diseases. Additionally, to explore the general characteristics of the studies included in the analysis, focusing on their key features and trends.

A comprehensive literature search was conducted from multiple online databases, including PubMed, Scopus, Web of Science, and CINAHL-EBSCO. The search strategy was designed to identify studies related to personalized cancer medicine and herbal interventions.

Publications pertaining to cancer research conducted through in vitro, in vivo, and clinical studies, employing natural products were included in this review.

Two review authors independently applied inclusion and inclusion criteria, data extraction, and assessments of methodological quality. The quality assessment and biases of the studies were evaluated based on modified Jadad scales. A detailed quantitative summary of the included studies is presented, providing a comprehensive description of their key features and findings.

A total of 121 studies were included in this review for analysis. Some of them were considered as comprehensive experimental investigations both in vitro and in vivo. The majority (n = 85) of the studies included in this review were conducted in vitro, with 44 of them specifically investigating the effects of herbal medicine on animal models. Additionally, 7 articles with a combined sample size of 31,271 patients, examined the impact of herbal medicine in clinical settings.

Personalized medication can optimize the use of herbal medicine in cancer treatment by considering individual patient factors such as genetics, medical history, and other treatments. Additionally, active phytochemicals found in herbs have shown potential for inhibiting cancer cell growth and inducing apoptosis, making them a promising area of research in preclinical and clinical investigations. Please cite this article as: Tayeb BA, Kusuma IY, Osman AAM, Minorics R. Herbal compounds as promising therapeutic agents in precision medicine strategies for cancer: A systematic review. J Integr Med. 2024; 22(2): 137-162.

Cancer immunotherapies aimed at activating immune system, especially by blocking immune checkpoints, have become a successful modality for treating patients with advanced cancers. However, its clinical practice is frequently conceded by high outcomes, low initial response rates and severe side effects. New strategies are necessary to complement and advance this biological therapy. Erzhi Pills (EZP) have diverse pharmaceutical effects including immune regulation, anti-tumor and anti-senescence. We hypothesized that EZP could exert its antitumor effect through immunomodulation.

The aim of this study was to investigate the effects of EZP on anti-tumor activities, and define its molecular mechanisms.

By applying melanoma model with high immune infiltrates, we determined the anti-melanoma effect of EZP. To identify whether this effect was mediated by direct targeting tumor cells, cell viability and apoptosis were examined in vitro. Network pharmacology analysis was used to predict the potential mechanisms of EZP for melanoma via immune response. Flow cytometry, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA) and crystal violet (CV) experiments were performed to detect T cell infiltrations and functions mediated by EZP. The mechanism of EZP was further investigated by western blotting both in vivo and in vitro.

The administration of EZP significantly inhibited tumor weight and volume. EZP extract could only slightly reduce cell viability and induce melanoma apoptosis. Network pharmacology analysis predicted that JAK-STAT signaling pathway and T cell receptor signaling pathway might be involved during EZP treatment. Flow cytometry and IHC analyses showed that EZP increased the number of CD4+ T cells and enhanced the function of CD8+ T cells. In co-culture experiments, EZP elevated killing ability of T cells. Western blotting showed that EZP treatment reduced PD-L1 signaling pathway.

These findings indicated that EZP exerted anti-melanoma effects by inducing apoptosis and blocking PD-L1 to activate T cells. EZP might represent a promising candidate drug for cancer immunotherapies.

Dandelion (Taraxacum mongolicum Hand.-Mazz), as a famous medicinal and edible plant, has the effects of clearing heat and detoxifying, diuresis, and resolving masses. Phytochemistry investigations revealed that T. mongolicum has various bioactive ingredients, mainly including flavonoids, sterols, polysaccharides, phenolic acids and volatile oils. There is growing evidence have shown that the polysaccharides from T. mongolicum (TMPs) are a class of representative pharmacologically bioactive macromolecules with a variety of biological activities both in vitro and in vivo, such as immunomodulatory, anti-inflammatory, anti-oxidant, anti-tumor, hepatoprotective, hypolipidemic and hypoglycemic, anti-bacterial, regulation of intestinal microbial, and anti-fatigue activities, etc. Additionally, the structural modification and potential applications of TMPs were also outlined. The present review aims to comprehensively and systematically collate the recent research progress on extraction and purification methods, structural characteristics, biological activities, mechanism of action, structural modification, and potential industry applications of TMPs to support their therapeutic potential and health care functions. Overall, the present review provides a theoretical overview for further development and utilization of TMPs in the fields of pharmaceutical and health food.

Hepatocellular carcinoma (HCC) is a challenging and very fatal liver cancer. The signal transducer and activator of transcription 3 (STAT3) pathway is a crucial regulator of tumor development and are ubiquitously active in HCC. Therefore, targeting STAT3 has emerged as a promising approach for preventing and treating HCC. Various natural bioactive compounds (NBCs) have been proven to target STAT3 and have the potential to prevent and treat HCC as STAT3 inhibitors. Numerous kinds of STAT3 inhibitors have been identified, including small molecule inhibitors, peptide inhibitors, and oligonucleotide inhibitors. Due to the undesirable side effects of the conventional therapeutic drugs against HCC, the focus is shifted to NBCs derived from plants and other natural sources. NBCs can be broadly classified into the categories of terpenes, alkaloids, carotenoids, and phenols. Most of the compounds belong to the family of terpenes, which prevent tumorigenesis by inhibiting STAT3 nuclear translocation. Further, through STAT3 inhibition, terpenes downregulate matrix metalloprotease 2 (MMP2), matrix metalloprotease 9 (MMP9) and vascular endothelial growth factor (VEGF), modulating metastasis. Terpenes also suppress the anti-apoptotic proteins and cell cycle markers. This review provides comprehensive information related to STAT3 abrogation by NBCs in HCC with in vitro and in vivo evidences.

Primarily sourced from Asteraceae family herbs such as the Dandelion, Taraxasterol is a pentacyclic triterpenoid lauded for its extensive biological functionalities. Its therapeutic potency is demonstrated in various disease models, encompassing enteritis, arthritis, acute hepatic injury, and pneumonia. Scientific literature underscores its anti-inflammatory, antioxidant, and antineoplastic attributes. The primary aim of this study is to thoroughly explore the diseasemodulating mechanisms and effects of taraxasterol. We endeavor to provide an exhaustive review of the experimental subjects, intervention components, distinct action modalities, contributing factors, and protein pathway expressions associated with taraxasterol, systematically represented via diagrams and tables. Such a schematic representation encourages a continued academic dialogue concerning taraxasterol's pharmacological characteristics. This review is envisioned as a practical guide for the selection of experimental subjects and methodologies in prospective research. It is intended to further illuminate taraxasterol's pharmacodynamics, thereby offering theoretical and empirical justification for its clinical application.

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection drove the global coronavirus disease 2019 (COVID-19) pandemic, causing a huge loss of human life and a negative impact on economic development. It is an urgent necessity to explore potential drugs against viruses, such as SARS-CoV-2. Silymarin, a mixture of herb-derived polyphenolic flavonoids extracted from the milk thistle, possesses potent antioxidative, anti-apoptotic, and anti-inflammatory properties. Accumulating research studies have demonstrated the killing activity of silymarin against viruses, such as dengue virus, chikungunya virus, and hepatitis C virus. However, the anti-COVID-19 mechanisms of silymarin remain unclear. In this study, multiple disciplinary approaches and methodologies were applied to evaluate the potential mechanisms of silymarin as an anti-viral agent against SARS-CoV-2 infection. In silico approaches such as molecular docking, network pharmacology, and bioinformatic methods were incorporated to assess the ligand-protein binding properties and analyze the protein-protein interaction network. The DAVID database was used to analyze gene functions, such as the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) enrichment. TCMSP and GeneCards were used to identify drug target genes and COVID-19-related genes. Our results revealed that silymarin compounds, such as silybin A/B and silymonin, displayed triplicate functions against SARS-CoV-2 infection, including directly binding with human angiotensin-converting enzyme 2 (ACE2) to inhibit SARS-CoV-2 entry into the host cells, directly binding with viral proteins RdRp and helicase to inhibit viral replication and proliferation, and regulating host immune response to indirectly inhibit viral infection. Specifically, the targets of silymarin molecules in immune regulation were screened out, such as proinflammatory cytokines TNF and IL-6 and cell growth factors VEGFA and EGF. In addition, the molecular mechanism of drug-target protein interaction was investigated, including the binding pockets of drug molecules in human ACE2 and viral proteins, the formation of hydrogen bonds, hydrophobic interactions, and other drug-protein ligand interactions. Finally, the drug-likeness results of candidate molecules passed the criteria for drug screening. Overall, this study demonstrates the molecular mechanism of silymarin molecules against SARS-CoV-2 infection.

In hepatocellular carcinoma (HCC), sorafenib (Sora) efficacy is limited by primary and/or acquired resistance. Emerging evidence shows that the inflammatory factor interleukin 6 (IL-6) plays a role in Sora resistance. Norcantharidin (NCTD), a derivative of cantharidine, was identified as a potent IL-6 inhibitor. Thus, in this study, we evaluated NCTD ability to improve the Sora efficacy in HCC and its underlying molecular mechanisms. Male Sprague Dawely rats were administered NCTD (0.1 mg/kg/day; orally) or Sora (10 mg/kg day; orally) or combination for 6 weeks after HCC induction using thioacetamide (200 mg/kg; ip; 2 times/wk) for 16 weeks. Our results showed that NCTD greatly enhanced Sora activity against HCC and potentiated Sora-induced oxidative stress. NCTD enhanced Sora-induced tumor immunity reactivation by decreasing both fibrinogen-like protein 1 level and increasing both tumor necrosis factor-α gene expression along with CD8+ T cells number. Also, NCTD augmented Sora attenuation activity against TAA-induced angiogenesis and metastasis by decreasing VEGFA, HIF-1α, serum lactate dehydrogenase enzyme, and vimentin levels. The combined use of NCTD/Sora suppressed drug resistance and stemness by downregulating ATP-binding cassette subfamily G member 2, neurogenic locus notch homolog protein, spalt-like transcription factor 4, and CD133. NCTD boosted Sora antiproliferative and apoptotic activities by decreasing Ccnd1 and BCL2 expressions along with increasing BAX and caspase-3 expressions. To our knowledge, this study represents the first study providing evidence for the potential novel therapeutic use of NCTD/Sora combination for HCC. Moreover, no previous studies have reported the effect of NCTD on FGL1.

Humans have been consuming medicinal plants (as herbs/ spices) to combat illness for centuries while ascribing beneficial effects predominantly to the plant/phytochemical constituents, without recognizing the power of obligatory resident microorganism' communities (MOCs) (live/dead bacteria, fungus, yeast, molds etc.) which remain after industrial microbial reduction methods. Very little is known about the taxonomic identity of residual antigenic microbial associated molecular patterns (MAMPs) debris in our botanical over the counter (OTC) products, which if present would be recognized as foreign (non-self) antigenic matter by host pattern recognition receptors (PRRs) provoking a host immune response; this the basis of vaccine adjuvants. As of today, only few research groups have removed the herbal MAMP biomass from herbs, all suggesting that immune activation may not be from the plant but rather its microbial biomass; a hypothesis we corroborate.

The purpose of this work was to conduct a high through put screening (HTPS) of over 2500 natural plants, OTC botanical supplements and phytochemicals to elucidate those with pro-inflammatory; toll like receptor 4 (TLR4) activating properties in macrophages.

The HTPS was conducted on RAW 264.7 cells vs. lipopolysaccharide (LPS) E. coli 0111:B4, testing iNOS / nitric oxide production ( NO 2 - ) as a perimeter endpoint. The data show not a single drug/chemical/ phytochemical and approximately 98 % of botanicals to be immune idle (not effective) with only 65 pro-inflammatory (hits) in a potency range of LPS. Method validation studies eliminated the possibility of false artifact or contamination, and results were cross verified through multiple vendors/ manufacturers/lot numbers by botanical species. Lead botanicals were evaluated for plant concentration of LPS, 1,3:1,6-β-glucan, 1,3:1,4-β-D-glucan and α-glucans; where the former paralleled strength in vitro. LPS was then removed from plants using high-capacity endotoxin poly lysine columns, where bioactivity of LPS null "plant" extracts were lost. The stability of E.Coli 0111:B4 in an acid stomach mimetic model was confirmed. Last, we conducted a reverse culture on aerobic plate counts (APCs) from select hits, with subsequent isolation of gram-negative bacteria (MacConkey agar). Cultures were 1) heat destroyed (retested/ confirming bioactivity) and 2) subject to taxonomical identification by genetic sequencing 18S, ITS1, 5.8 s, ITS2 28S, and 16S.

The data show significant gram negative MAMP biomass dominance in A) roots (e.g. echinacea, yucca, burdock, stinging nettle, sarsaparilla, hydrangea, poke, madder, calamus, rhaponticum, pleurisy, aconite etc.) and B) oceanic plants / algae's (e.g. bladderwrack, chlorella, spirulina, kelp, and "OTC Seamoss-blends" (irish moss, bladderwrack, burdock root etc), as well as other random herbs (eg. corn silk, cleavers, watercress, cardamom seed, tribulus, duckweed, puffball, hordeum and pollen). The results show a dominance of gram negative microbes (e.g. Klebsilla aerogenes, Pantoae agglomerans, Cronobacter sakazakii), fungus (Glomeracaea, Ascomycota, Irpex lacteus, Aureobasidium pullulans, Fibroporia albicans, Chlorociboria clavula, Aspergillus_sp JUC-2), with black walnut hull, echinacea and burdock root also containing gram positive microbial strains (Fontibacillus, Paenibacillus, Enterococcus gallinarum, Bromate-reducing bacterium B6 and various strains of Clostridium).

This work brings attention to the existence of a functional immune bioactive herbal microbiome, independent from the plant. There is need to further this avenue of research, which should be carried out with consideration as to both positive or negative consequences arising from daily consumption of botanicals highly laden with bioactive MAMPS.

In our previous studies, we used a graded alcohol precipitation method to extract four maca polysaccharide components (MCP1, MCP2, MCP3, and MCP4) from maca with various molecular weights. Compared to other three components, MCP2 had stronger immunoregulatory abilities on CD4⁺T cells. To avoid the immunosuppressive effect of 5-fluorouracil (5-FU), maca polysaccharides in combination with 5-FU treatment were investigated in this study. The results show that 500 mg/kg and 1000 mg/kg MCP2 could significantly delay the growth of tumor and enhance the anti-tumor effect of 5-FU in vivo. Furthermore, MCP2 can partly recover the proliferation of CD4⁺T cells after being suppressed by 5-FU in vitro. Additionally, in order to explore the mechanism in which MCP2 acts on CD4⁺T cells, the MCP2 is marked with FITC fluorescence and synthesis MCP2-Tyr-FITC for the first time. Confocal microscope results show that MCP2-Tyr-FITC can directly bind to the surface of CD4⁺T cells. Together, our work demonstrates that maca polysaccharides could enhance the anti-tumor effect when combined with 5-FU by regulating CD4⁺T cells, suggesting a novel potential immunomodulator in tumor therapy.

Chronic liver disease (CLD) is a continuous process that causes a reduction of liver function lasting more than six months. CLD includes alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), chronic viral infection, and autoimmune hepatitis, which can lead to liver fibrosis, cirrhosis, and cancer. Liver inflammation and oxidative stress are commonly associated with the development and progression of CLD. Molecular signaling pathways such as AMP-activated protein kinase (AMPK), C-Jun N-terminal kinase, and peroxisome proliferator-activated receptors (PPARs) are implicated in the pathogenesis of CLD. Therefore, antioxidant and anti-inflammatory agents from natural products are new potent therapies for ALD, NAFLD, and hepatocellular carcinoma (HCC). In this review, we summarize some powerful products that can be potential applied in all the stages of CLD, from ALD/NAFLD to HCC. The selected agents such as β-sitosterol, curcumin, genistein, and silymarin can regulate the activation of several important molecules, including AMPK, Farnesoid X receptor, nuclear factor erythroid 2-related factor-2, PPARs, phosphatidylinositol-3-kinase, and lysyl oxidase-like proteins. In addition, clinical trials are undergoing to evaluate their efficacy and safety.

Hepatocellular carcinoma (HCC), the most prevalent subtype of liver cancer, is the second main reason for cancer-related deaths worldwide. In recent decades, sufficient evidence supported that immunotherapy was a safe and effective treatment option for HCC. However, tolerance and frequent recurrence and metastasis occurred in patients after immunotherapy due to the complicated crosstalk in the tumor immunosuppressive microenvironment (TIME) in HCC. Therefore, elucidating the TIME in HCC and finding novel modulators to target TIME for attenuating immune suppression is critical to optimize immunotherapy. Recently, studies have shown the potentially immunoregulatory activities of natural compounds, characterized by multiple targets and pathways and low toxicity. In this review, we concluded the unique role of TIME in HCC. Moreover, we summarized evidence that supports the hypothesis of natural compounds to target TIME to improve immunotherapy. Furthermore, we discussed the comprehensive mechanisms of these natural compounds in the immunotherapy of HCC. Accordingly, we present a well-grounded review of the naturally occurring compounds in cancer immunotherapy, expecting to shed new light on discovering novel anti-HCC immunomodulatory drugs from natural sources.

Hepatocellular carcinoma (HCC) is the most common and serious type of primary liver cancer. HCC patients have a high death rate and poor prognosis due to the lack of clear signs and inadequate treatment interventions. However, the molecular pathways that underpin HCC pathogenesis remain unclear. Long non-coding RNAs (lncRNAs), a new type of RNAs, have been found to play important roles in HCC. LncRNAs have the ability to influence gene expression and protein activity. Dysregulation of lncRNAs has been linked to a growing number of liver disorders, including HCC. As a result, improved understanding of lncRNAs could lead to new insights into HCC etiology, as well as new approaches for the early detection and treatment of HCC. The latest results with respect to the role of lncRNAs in controlling multiple pathways of HCC were summarized in this study. The processes by which lncRNAs influence HCC advancement by interacting with chromatin, RNAs, and proteins at the epigenetic, transcriptional, and post-transcriptional levels were examined. This critical review also highlights recent breakthroughs in lncRNA signaling pathways in HCC progression, shedding light on the potential applications of lncRNAs for HCC diagnosis and therapy.