Epigenetic and metabolic reprogramming alterations are two important features of tumors, and their reversible, spatial, and temporal regulation is a distinctive hallmark of carcinogenesis. Epigenetics, which focuses on gene regulatory mechanisms beyond the DNA sequence, is a new entry point for tumor therapy. Moreover, metabolic reprogramming drives hepatocellular carcinoma (HCC) initiation and progression, highlighting the significance of metabolism in this disease. Exploring the inter-regulatory relationship between tumor metabolic reprogramming and epigenetic modification has become one of the hot directions in current tumor metabolism research. As viral etiologies have given way to metabolic dysfunction-associated steatotic liver disease (MASLD)-induced HCC, it is urgent that complex molecular pathways linking them and hepatocarcinogenesis be explored. However, how aberrant crosstalk between epigenetic modifications and metabolic reprogramming affects MASLD-induced HCC lacks comprehensive understanding. A better understanding of their linkages is necessary and urgent to improve HCC treatment strategies. For this reason, this review examines the interwoven landscape of molecular carcinogenesis in the context of MASLD-induced HCC, focusing on mechanisms regulating aberrant epigenetic alterations and metabolic reprogramming in the development of MASLD-induced HCC and interactions between them while also updating the current advances in metabolism and epigenetic modification-based therapeutic drugs in HCC.

Background: Carthamus tinctorius L. has a long history of ethnomedicinal use for various ailments. This review focuses on the botany, ethnopharmacology, phytochemistry, pharmacological effects, and clinical applications of safflower, aiming to enhance current research in this field.Methods: The study incorporated relevant scientific literature up to April 2025. It involved the collection of both Chinese and English studies on safflower from various databases, including PubMed, Elsevier, Web of Science, Springer, ScienceDirect, Wiley, ACS, and CNKI (China National Knowledge Infrastructure). Additionally, doctoral and master’s dissertations were included in the analysis.Results: From 1978 to April 2025, various active metabolites were identified, primarily comprising flavonoids, polyacetylenes, and alkaloids, with flavonoids being the predominant group. Extracts and metabolites derived from safflower have demonstrated a range of bioactivities, including antioxidant, hepatoprotective, anti-inflammatory, and anticancer effects. In clinical practice, the effective components of safflower have been utilized in the treatment of cardiovascular and cerebrovascular diseases, diabetes, hepatobiliary conditions, poor blood circulation, sudden deafness, and other ailments.Conclusion: This review elucidates the research surrounding safflower in the domains of ethnopharmacology, phytochemistry, pharmacological activity, and clinical applications. Safflower is known to contain a diverse array of compounds, with flavonoids in particular demonstrating significant pharmacological activity. These compounds are extensively utilized in the pharmaceutical, food, and cosmetic industries, positioning safflower as a promising candidate for development and application in the treatment of various diseases. Nonetheless, research on safflower remains limited, and many active metabolites have yet to be thoroughly investigated in terms of their phytochemical and pharmacological properties. To date, only a handful of active metabolites have been isolated and assessed for their biological activity, and there is a notable deficiency in research regarding their mechanisms of action. Therefore, comprehensive studies are imperative to enhance our understanding of safflower and to substantiate its therapeutic potential.

Naringenin (NRG) is a natural flavonoid compound abundantly present in citrus fruits and has the potential to treat respiratory disorders. However, the clinical therapeutic effect of NRG is limited by its low bioavailability due to poor solubility. To enhance the solubility, naringenin nanosuspensions (NRG-NSps) were prepared by applying tocopherol polyethylene glycol succinate (TPGS) as the nanocarrier via the media-milling method. The particle size, morphology, and drug-loading content of NRG-NSps were examined, and the stability was evaluated by detecting particle size changes in different physiological media. NRG-NSps exhibited a flaky appearance with a mean diameter of 216.9 nm, and the drug-loading content was 66.7%. NRG-NSps exhibited good storage stability and media stability. NRG-NSps presented a sustainable release profile, and the cumulative drug-release rate approached approximately 95% within 7 d. NRG-NSps improved the antitussive effect significantly compared with the original NRG, the cough frequency was decreased from 22 to 15 times, and the cough incubation period was prolonged from 85.3 to 121.6 s. Besides, NRG-NSps also enhanced expectorant effects significantly, and phenol red secretion was increased from 1.02 to 1.45 μg/mL. These results indicate that NRG-NSps could enhance the bioavailability of NRG significantly and possess a potential clinical application.

Purpose: Macrophages play a pivotal role in rheumatoid arthritis (RA) pathogenesis. Paeoniflorin, a traditional Chinese medication, reduces inflammation by suppressing immune cell activation and inducing synovial fibroblast apoptosis, attenuating RA disease progression. Despite the potential therapeutic benefits, free paeoniflorin has limitations, including low drug utilization, poor selectivity, and short half-life during administration. We aimed to develop and evaluate dextran sulfate-modified paeoniflorin pH-responsive lipid–polymer hybrid nanoparticles (Pae–PPNPs–DS) for targeted macrophage delivery and improved treatment efficacy in RA. The pH sensitivity is attributed to the incorporation of poly(cyclohexane-1,4-dimethylene ketal), which undergoes hydrolysis-triggered degradation under acidic conditions enabling passive targeting to inflammatory sites through pH-dependent drug release. Simultaneously, dextran sulfate serves as a ligand to actively target Scavenger receptor class A type I overexpressed on activated macrophages in RA synovium, achieving dual-targeted delivery via environmental responsiveness and ligand-receptor interaction. Methods: We developed dextran sulfate-modified Pae–PPNPs–DS, which exhibits dual capabilities of active macrophage targeting and pH-triggered drug release, to deliver paeoniflorin to macrophages and improve drug delivery at the joint inflammation site. Nanoparticle characterization, in vitro release behavior, stability, macrophage uptake, macrophage polarization pathway, phenotypic polarization, and therapeutic efficacy were evaluated in a rat model of RA. Results: Pae–PPNPs–DS had smooth surfaces, uniform particle sizes, physical stability, and pH-responsive characteristics. RAW264.7 macrophages showed enhanced Pae–PPNPs–DS uptake. Pae–PPNPs–DS effectively modulated the STAT signaling pathway and modulated macrophage polarization. Pae–PPNPs–DS inhibited the expression of TNF-α/IL-1β/iNOS/IL-6 (pro-inflammatory and M1 markers), while promoting IL-10/Arg-1/TGF-β (anti-inflammatory and M2 markers) secretion. Pathological analysis revealed that Pae–PPNPs–DS prevented synovial tissue proliferation, inhibited inflammatory cell infiltration, and exhibited therapeutic efficacy. Conclusion: Pae–PPNPs–DS actively target macrophages, regulate polarization through STAT pathway, and inhibit joint inflammation, suggesting its potential in treating RA. The study highlights the potential of pH-responsive nanocarriers as an innovative approach to treating autoimmune diseases. Plain Language Summary: Rheumatoid arthritis (RA) is a chronic condition that causes painful swelling and damage to the joints and is driven in part by overactive immune cells called macrophages, which produce harmful inflammation. Current treatments for RA can be expensive and have significant side effects, highlighting the need for new, safer therapies. Our study focused on improving how a natural compound called paeoniflorin is delivered to the inflamed joints of people with RA. Paeoniflorin has anti-inflammatory properties, but it does not last long in the body and is not very effective on its own. To address this, we developed tiny, specially designed carriers called nanoparticles to deliver paeoniflorin directly to the inflamed areas of the joints. These nanoparticles are coated with a material that helps them target macrophages and release the drug when they reach the acidic environment of the inflamed tissue. We tested our nanoparticles in vitro and in vivo with RA-like symptoms. The results were promising: the nanoparticles were endocytosed by macrophages, reduced harmful inflammation, and promoted healing. In rats, these nanoparticles reduced joint swelling and tissue damage more effectively than the drug on its own. They also showed good safety and stability. These findings suggest that this new delivery system could be a more effective and targeted way to treat RA, reducing the inflammation and pain caused by the disease while avoiding some of the side effects of current treatments. This approach could lead to better outcomes for people living with RA.