1.Molecular Mechanisms of Salvia Miltiorrhiza and Its Active Ingredients against Colorectal Cancer: A Review
Jianing GUO ; Xiaochen NI ; Kaiyuan ZHANG ; Wei FAN ; Chuhang WANG ; Chao XU ; Jianbo HUANG ; Tao JIANG ; Guangji ZHANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(4):307-314
Colorectal cancer (CRC) is one of the most common cancers, with its incidence ranking high among cancers. It stands as the second leading cause of cancer-related death worldwide. In the early stages, CRC lacks specific symptoms, and most patients are diagnosed at advanced stages, making it a major research focus in the field of gastrointestinal tumors. Currently, clinical CRC treatments face several common challenges, including high surgical risks, frequent metastasis and recurrence, drug resistance, and significant side effects from chemotherapy and radiation therapy. With the development and application of traditional Chinese medicine (TCM), it has been found that TCM and its active ingredients can effectively inhibit CRC cell proliferation, invasion, migration, and angiogenesis, and promote apoptosis and autophagy, thereby slowing the progression of CRC. This has become a key focus of CRC treatment research. Salvia Miltiorrhiza has multiple pharmacological effects, including activating blood circulation to dispel blood stasis, unlocking meridians to relieve pain, clearing heat to calm irritability, and cooling blood to reduce abscesses. It contains a variety of chemical components, including diterpenoids, phenolic acids, flavonoids, polysaccharides, nitrogen-containing compounds, steroids, and lactone compounds. This review summarized the molecular mechanisms of Salvia miltiorrhiza and its active ingredients in the treatment of CRC. It is found that these ingredients exert anti-CRC effects through various molecular mechanisms, including cell cycle arrest, promotion of apoptosis, inhibition of cell invasion and migration, induction of autophagy, suppression of tumor angiogenesis, and remodeling of the tumor microenvironment. The review aims to provide new insights for the drug development and clinical application of Salvia miltiorrhiza in CRC treatment.
2.Evaluation of the anticoagulant effect of nafamostat mesylate in continuous veno-venous hemofiltration with different dilution methods for uremic patients
Li SHEN ; Yao ZHANG ; Jun WANG ; Hong ZHU ; Yong QIN ; Yuewu TANG ; Ni DU
China Pharmacy 2026;37(3):350-355
OBJECTIVE To evaluate the anticoagulant efficacy and safety of nafamostat mesylate (NM) in the treatment of uremic patients at high risk of bleeding undergoing continuous veno-venous hemofiltration (CVVH) with different methods (pre- dilution and post-dilution). METHODS A total of 130 uremic patients at high risk of bleeding who underwent CVVH treatment in the nephrology department of Chongqing University Three Gorges Hospital from July 2023 to September 2024 were selected. They were divided into pre-dilution group and post-dilution group according to the random number table method, with 65 cases in each group. Both groups of patients received CVVH treatment under NM anticoagulation. The pre-dilution group adopted the pre-dilution replacement method, while the post-dilution group adopted the post-dilution replacement method. The coagulation, pressure, and usage duration of the filter and dialysis circuit venous reservoirs were compared between the two groups. The changes in prothrombin time (PT), prothrombin time-international normalized ratio (PT-INR), activated partial thromboplastin time (APTT), and fibrinogen (FIB) in the peripheral venous blood before the heparin pump and after the filter at 1, 4 and 7 h of CVVH treatment, as well as 20 min after the end of treatment, were compared between the two groups. The single-compartment urea clearance rate (spKt/V), β2-microglobulin (β2-MG) clearance rate and the incidence of adverse reactions were duni2007@foxmail.com compared between the two groups. RESULTS Both the pre-dilution and post-dilution groups had 60 patients who completed the study. The incidence of grade Ⅱ-Ⅲ coagulation of the filter and venous reservoirs, as well as the number of patients with transmembrane and venous pressure alarm intervention in the post- dilution group were significantly higher or more than those in the pre-dilution group (P<0.05), while usage time of the filter and the pipeline in the post-dilution group was significantly shorter than that in the pre-dilution group (P<0.05). The APTT values before the heparin pump as well as PT and APTT values after the filter at 1 h, 4 h, and 7 h of CVVH treatment in the post-dilution group were significantly higher than those in the pre-dilution group (P<0.001). There were no significant differences in PT, PT- INR, APTT and FIB between the two groups of patients 20 min after the end of treatment (P>0.05). The spKt/v and β2-MG clearance rates in the post-dilution group were significantly higher than those in the pre-dilution group (P<0.001). There was no significant difference in the incidence of adverse reactions between the two groups (P>0.05). CONCLUSIONS When NM is used as an anticoagulant in the CVVH treatment of uremic patients at high risk of bleeding, compared with the pre-dilution treatment method, the post-dilution treatment method has a higher incidence of filter and dialysis tubing venous reservoir, a shorter usage time of the filter and pipeline, and a greater impact on extracorporeal coagulation, but has a higher solute clearance rate. Clinically, different dilution methods can be selected according to the different treatment needs of patients.
3.Mechanism of Diaphragmatic Dysfunction in Chronic Obstructive Pulmonary Disease and Treatment with Traditional Chinese Medicine: A Review
Yuanyuan YING ; Xiaoqing ZHOU ; Kaiwen NI ; Zhen WANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(8):285-296
Chronic obstructive pulmonary disease(COPD) is a common chronic respiratory disorder frequently accompanied by diaphragmatic dysfunction during its course, which significantly increases respiratory burden and impairs quality of life. As the primary inspiratory muscle, the diaphragm is prone to fatigue, atrophy, inflammation, and fibrosis during the long-term progression of COPD. Its pathological mechanisms involve multiple pathways such as inflammatory responses, oxidative stress, mitochondrial dysfunction, apoptosis, ion channel abnormalities, epigenetic regulation, autophagy disorder, and protein metabolism imbalance. In recent years, traditional Chinese medicine(TCM) has demonstrated multi-targeted and systemic regulatory advantages in improving diaphragmatic function in COPD. However, related studies remain fragmented, and integrated mechanistic understanding is lacking. This paper focuses on the mechanism-target-TCM intervention framework, systematically summarizing the molecular mechanisms of diaphragmatic dysfunction, while incorporating the TCM theory of Zongqi(ancestral Qi). It highlights the therapeutic effects of Chinese herbal formulas, single herbs, and active components in modulating inflammation, oxidative stress, mitochondrial function, ion channels, epigenetic processes, autophagy, and protein homeostasis. Additionally, the review outlines existing challenges, including insufficient study volume, unbalanced selection of herbal prescriptions, limited mechanistic depth, inconsistent disease models and experimental designs, lack of standardized diaphragmatic function assessment, and weak clinical validation. Future research should strengthen the integration of TCM and modern medicine, identify additional therapeutic targets, deepen mechanistic research, and establish unified and standardized experimental systems to advance the theoretical foundation and clinical application of TCM in the prevention and treatment of COPD-related diaphragmatic dysfunction.
4.Mechanism of Diaphragmatic Dysfunction in Chronic Obstructive Pulmonary Disease and Treatment with Traditional Chinese Medicine: A Review
Yuanyuan YING ; Xiaoqing ZHOU ; Kaiwen NI ; Zhen WANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(8):285-296
Chronic obstructive pulmonary disease(COPD) is a common chronic respiratory disorder frequently accompanied by diaphragmatic dysfunction during its course, which significantly increases respiratory burden and impairs quality of life. As the primary inspiratory muscle, the diaphragm is prone to fatigue, atrophy, inflammation, and fibrosis during the long-term progression of COPD. Its pathological mechanisms involve multiple pathways such as inflammatory responses, oxidative stress, mitochondrial dysfunction, apoptosis, ion channel abnormalities, epigenetic regulation, autophagy disorder, and protein metabolism imbalance. In recent years, traditional Chinese medicine(TCM) has demonstrated multi-targeted and systemic regulatory advantages in improving diaphragmatic function in COPD. However, related studies remain fragmented, and integrated mechanistic understanding is lacking. This paper focuses on the mechanism-target-TCM intervention framework, systematically summarizing the molecular mechanisms of diaphragmatic dysfunction, while incorporating the TCM theory of Zongqi(ancestral Qi). It highlights the therapeutic effects of Chinese herbal formulas, single herbs, and active components in modulating inflammation, oxidative stress, mitochondrial function, ion channels, epigenetic processes, autophagy, and protein homeostasis. Additionally, the review outlines existing challenges, including insufficient study volume, unbalanced selection of herbal prescriptions, limited mechanistic depth, inconsistent disease models and experimental designs, lack of standardized diaphragmatic function assessment, and weak clinical validation. Future research should strengthen the integration of TCM and modern medicine, identify additional therapeutic targets, deepen mechanistic research, and establish unified and standardized experimental systems to advance the theoretical foundation and clinical application of TCM in the prevention and treatment of COPD-related diaphragmatic dysfunction.
5.Antibiotic exposure among third grade primary school students in Shenzhen
NI Yiping, ZHU Bo, ZHANG Wen, WANG Li, JI Xiang
Chinese Journal of School Health 2026;47(3):438-442
Objective:
To investigate the status of antibiotic exposure in third grade primary school students in Shenzhen,so as to provide evidence for the scientific management of antibiotic use and reduction of population health risks.
Methods:
From 1 September to 30 October 2021, 200 third grade students from 8 primary schools in Luohu District of Shenzhen were selected by cluster random sampling as research subjects. The body composition was measured, urine samples were collected, and the contents of 35 antibiotics in the samples were detected by mass spectrometry. Relevant dietary habit information of the subjects was collected via questionnaires. The Chi square test was used to compare the detection rate of antibiotics among different genders and weight grades. The Logistic regression model was adopted to evaluate the correlation between the target antibiotic detection rate and dietary habits.
Results:
At least one type of antibiotic was detected in 198 of the subjects with an overall detection rate of 99.0% . Among the 35 target antibiotics, 23 were detected with detection rates ranging from 0.5%-69.5%. Quinolones had the highest detection rate of 86.5% , followed by macrolides and sulfonamides with detection rates of 77.5% and 76.5%, respectively. The detection rate of antibiotics was 98.3% in boys and 100.0% in girls with no statistically significant difference ( χ 2=1.35, P >0.05). The detection rates of quinolones, macrolides, and sulfonamides varied significantly among children with different BMI categories ( χ 2=38.18, 12.45, 9.76 , all P <0.05). The multivariate Logistic regression model analysis showed that the macrolide detection rate was affected by genders( OR =0.42) and the sulfonamide detection rate was significantly correlated with the frequency of dairy product consumption and being overweight( OR =2.01)(both P <0.05). Enrofloxacin was associated with the weekly consumption frequency of livestock meat such as pork, beef and mutton, as well as the weekly consumption frequency of poultry meat such as chicken, duck and goose ( OR = 2.81,2.17,both P <0.05). Trimethoprim was associated with the weekly frequency of drinking pure milk ( OR =5.49, P < 0.05 ).
Conclusions
Third grade primary school students in Shenzhen are generally exposed to low dose antibiotics. Macrolides, quinolones, and sulfonamides may be associated with the risk of obesity in primary school students.
6.Analysis of factors influencing the achievement of target vancomycin plasma concentration and construction of a predictive model in patients from high-altitude regions: a single-center retrospective study
Ya’e CHANG ; NI ZHAO ; Zhilan HUAN ; Guiqin XU ; Xue WU ; Yafeng WANG
China Pharmacy 2026;37(2):198-203
OBJECTIVE To analyze the influencing factors for achieving target plasma drug concentration (trough) (abbreviated as “PDC”) of vancomycin in patients from high-altitude regions and establish a predictive model for PDC using single- center data, providing references for rational clinical drug use. METHODS Inpatients with vancomycin (1 g, q12 h) administered intravenously in our hospital from January 2021 to June 2024 were retrospectively included. Demographic data, liver and kidney function and hematological indexes were collected. Spearman correlation analysis was used to evaluate the correlation between vancomycin PDC and each detection index. Univariate analysis was used to evaluate the differences of each index in patients with different PDC, and the effects of different gender, body mass index, age and underlying diseases (hypertension/diabetes) on vancomycin PDC. Based on the results of correlation analysis and univariate analysis, multiple linear stepwise regression analysis was used to obtain the independent predictors of vancomycin PDC and construct the prediction model. RESULTS A total of 141 patients were included, with an overall attainment rate of 46.81% for the target PDC of vancomycin. Correlation analysis showed that the vancomycin PDC was positively correlated with age, blood urea nitrogen, uric acid (UA), serum creatinine (CRE) and β2- microglobulin (β2-MG), and negatively correlated with height, weight, creatinine clearance rate (CCR), glomerular filtration rate (GFR), alanine transaminase (ALT), hemoglobin (HGB), white blood cell count and neutrophils (P<0.05). There were significant differences in age, CRE and other 14 indexes among different PDC groups (P<0.05 or P<0.01). Age and underlying diseases had significant effects on vancomycin PDC (P<0.05 or P<0.01). CCR, direct bilirubin (DBil), β2-MG, UA, HGB and height (standardized coefficients were -0.371, 0.367, 0.169, 0.232, -0.140, -0.132; P<0.05) were independent predictors of vancomycin PDC. The F value of the regression equation was 34.858 (P<0.05), the R2 was 0.610, and the adjusted R2 was 0.592. CONCLUSIONS The vancomycin PDC of patients in high-altitude regions is affected by multiple factors such as renal function, liver function and hematological indexes. CCR, HGB and height could be used to predict vancomycin PDC negatively, while DBil, β2-MG and UA could be used to predict vancomycin PDC positively. The variables of the established prediction model could explain 59.2% of the variation of vancomycin PDC.
7.Clinical Advantages of Traditional Chinese Medicine in Treatment of Childhood Simple Obesity: Insights from Expert Consensus
Qi ZHANG ; Yingke LIU ; Xiaoxiao ZHANG ; Guichen NI ; Heyin XIAO ; Junhong WANG ; Liqun WU ; Zhanfeng YAN ; Kundi WANG ; Jiajia CHEN ; Hong ZHENG ; Xinying GAO ; Liya WEI ; Qiang HE ; Qian ZHAO ; Huimin SU ; Zhaolan LIU ; Dafeng LONG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(6):238-245
Childhood simple obesity has become a significant public health issue in China. Modern medicine primarily relies on lifestyle interventions and often suffers from poor long-term compliance, while pharmacological options are limited and associated with potential adverse effects. Traditional Chinese Medicine (TCM) has a long history in the prevention and management of this condition, demonstrating eight distinct advantages, including systematic theoretical foundation, diversified therapeutic approaches, definite therapeutic efficacy, high safety profile, good patient compliance, comprehensive intervention strategies, emphasis on prevention, and stepwise treatment protocols. Additionally, TCM is characterized by six distinctive features: the use of natural medicinal substances, non-invasive external therapies, integration of medicinal dietetics, simple exercise regimens, precise syndrome differentiation, and diverse dosage forms. By combining internal and external treatments, TCM facilitates individualized regimen adjustment and holistic regulation, demonstrating remarkable effects in improving obesity-related metabolic indicators, regulating constitutional imbalance, and promoting healthy behaviors. However, challenges remain, such as inconsistent operational standards, insufficient high-quality clinical evidence, and a gap between basic research and clinical application. Future efforts should focus on accelerating the standardization of TCM diagnosis and treatment, conducting multicenter randomized controlled trials, and fostering interdisciplinary integration, so as to enhance the scientific validity and international recognition of TCM in the prevention and treatment of childhood obesity.
8.Assessing High-density Y-SNP Panels for Paternal Haplogroup Assignment in Forensic Practice
De-Qin ZHANG ; Chun-Nian WANG ; Lin-Lin LOU ; Meng NI ; Jing GAO ; Jiang HUANG ; Li JIANG
Progress in Biochemistry and Biophysics 2026;53(2):458-469
ObjectiveThe accuracy of Y-chromosome haplogroup assignment is crucial for tracing paternal lineage in male samples. With the advancement of high-throughput sequencing technologies, high-density Y-SNP genotyping from whole-genome or array-based data has become a standard method for determiningY-chromosome haplogroups. This study systematically evaluated the performance of 4 commonly used high-density SNP genotyping systems—namely, the Global Screening Array (GSA), Chinese Genotyping Array (CGA), Affymetrix array, and the 1240K capture panel—for haplogroup assignment. This work provides a reference for data comparison across different systems. MethodsWe extracted genotype data for the 4 Y-SNP panels from 30× whole-genome sequencing (WGS) data of 1 590 male samples from the 1000 Genomes Project. Additionally, GSA array genotype data from 384 relative pairs (spanning 1st- to 12th-degree relationships) from 109 Chinese Han families were collected. Haplogroup assignment was performed using Y-LineageTracker v1.3.0 software. We assessed the concordance and resolution of haplogroup assignments between the four Y-SNP panels and the WGS data. The consistency and resolution of haplogroup assignments were also evaluated for both the 1000 Genomes Project samples and the 109 family samples collected in this study. Furthermore, the impact of varying numbers of Y-SNPs on haplogroup assignment was examined. ResultsThe GSA and CGA panels demonstrated superior resolution and discrimination of haplogroup subclades compared with the other two panels. The haplogroup assignments from the GSA, CGA, and 1240K panels showed high concordance with WGS data, with consistency rates exceeding 88.70%, whereas the Affymetrix platform exhibited a significantly lower consistency rate of 61.89%. Specifically, the GSA and CGA panels consistently demonstrated superior performance compared with the other two panels in the assignment of haplogroups O-M175 and H-L901, achieving complete concordance (100%) for both haplogroups. In contrast, the Affymetrix panel erroneously assigned all individuals belonging to haplogroup O-M175 to haplogroup K2-M526. Furthermore, its accuracy for haplogroup H-L901 was exceedingly low, at merely 1.41%. This poor performance was characterized by the misassignment of 98.59% of H-L901 samples—specifically, 1.41% to J-M304 and a predominant 97.18% to F-M89. For haplogroup R-M207, all four panels exhibited uniformly high levels of consistency, with concordance values exceeding 94.00%. Notably, for haplogroup E-M96, the 1240K and Affymetrix panels outperformed the GSA and CGA panels in terms of concordance, representing the first instance in which these two panels surpassed the latter. Conversely, for haplogroups J-M304, Q-M242, and I-M170, all 4 panels showed relatively elevated misclassification rates, with the Affymetrix array demonstrating the poorest overall performance. None of the four panels showed any discordant haplogroup assignments among the familial relative pairs analyzed. A positive correlation was observed between the number of Y-SNPs (ranging from 1 000 to 10 000) and classification consistency; however, classification consistency plateaued when the number of Y-SNPs exceeded 10 000. Furthermore, a random sampling analysis conducted on the GSA and CGA panels demonstrated that the haplogroup misclassification rate exhibited negligible fluctuation across the Y-SNP range of 500 to 1 000. Conversely, a marked enhancement in classification consistency was observed as the number of markers increased from 1 000 to 5 000, ultimately reaching a plateau within the interval of 5 000 to 8 000 markers. ConclusionThese findings indicate that the GSA and CGA panels provide high resolution and concordance, delivering reliable Y-haplogroup assignment for forensic investigations.
9.Assessing High-density Y-SNP Panels for Paternal Haplogroup Assignment in Forensic Practice
De-Qin ZHANG ; Chun-Nian WANG ; Lin-Lin LOU ; Meng NI ; Jing GAO ; Jiang HUANG ; Li JIANG
Progress in Biochemistry and Biophysics 2026;53(2):458-469
ObjectiveThe accuracy of Y-chromosome haplogroup assignment is crucial for tracing paternal lineage in male samples. With the advancement of high-throughput sequencing technologies, high-density Y-SNP genotyping from whole-genome or array-based data has become a standard method for determiningY-chromosome haplogroups. This study systematically evaluated the performance of 4 commonly used high-density SNP genotyping systems—namely, the Global Screening Array (GSA), Chinese Genotyping Array (CGA), Affymetrix array, and the 1240K capture panel—for haplogroup assignment. This work provides a reference for data comparison across different systems. MethodsWe extracted genotype data for the 4 Y-SNP panels from 30× whole-genome sequencing (WGS) data of 1 590 male samples from the 1000 Genomes Project. Additionally, GSA array genotype data from 384 relative pairs (spanning 1st- to 12th-degree relationships) from 109 Chinese Han families were collected. Haplogroup assignment was performed using Y-LineageTracker v1.3.0 software. We assessed the concordance and resolution of haplogroup assignments between the four Y-SNP panels and the WGS data. The consistency and resolution of haplogroup assignments were also evaluated for both the 1000 Genomes Project samples and the 109 family samples collected in this study. Furthermore, the impact of varying numbers of Y-SNPs on haplogroup assignment was examined. ResultsThe GSA and CGA panels demonstrated superior resolution and discrimination of haplogroup subclades compared with the other two panels. The haplogroup assignments from the GSA, CGA, and 1240K panels showed high concordance with WGS data, with consistency rates exceeding 88.70%, whereas the Affymetrix platform exhibited a significantly lower consistency rate of 61.89%. Specifically, the GSA and CGA panels consistently demonstrated superior performance compared with the other two panels in the assignment of haplogroups O-M175 and H-L901, achieving complete concordance (100%) for both haplogroups. In contrast, the Affymetrix panel erroneously assigned all individuals belonging to haplogroup O-M175 to haplogroup K2-M526. Furthermore, its accuracy for haplogroup H-L901 was exceedingly low, at merely 1.41%. This poor performance was characterized by the misassignment of 98.59% of H-L901 samples—specifically, 1.41% to J-M304 and a predominant 97.18% to F-M89. For haplogroup R-M207, all four panels exhibited uniformly high levels of consistency, with concordance values exceeding 94.00%. Notably, for haplogroup E-M96, the 1240K and Affymetrix panels outperformed the GSA and CGA panels in terms of concordance, representing the first instance in which these two panels surpassed the latter. Conversely, for haplogroups J-M304, Q-M242, and I-M170, all 4 panels showed relatively elevated misclassification rates, with the Affymetrix array demonstrating the poorest overall performance. None of the four panels showed any discordant haplogroup assignments among the familial relative pairs analyzed. A positive correlation was observed between the number of Y-SNPs (ranging from 1 000 to 10 000) and classification consistency; however, classification consistency plateaued when the number of Y-SNPs exceeded 10 000. Furthermore, a random sampling analysis conducted on the GSA and CGA panels demonstrated that the haplogroup misclassification rate exhibited negligible fluctuation across the Y-SNP range of 500 to 1 000. Conversely, a marked enhancement in classification consistency was observed as the number of markers increased from 1 000 to 5 000, ultimately reaching a plateau within the interval of 5 000 to 8 000 markers. ConclusionThese findings indicate that the GSA and CGA panels provide high resolution and concordance, delivering reliable Y-haplogroup assignment for forensic investigations.
10.The Role and Regulatory Mechanisms of FOXO1 in Hepatic Lipid Deposition
Meng JIA ; Fang-Hui LI ; Shi-Zhan YAN ; Ai-Ju LI ; Yi-Le WANG ; Pin-Shi NI ; Jia-Han HE ; Yin-Lu LI
Progress in Biochemistry and Biophysics 2026;53(4):905-919
Metabolic associated fatty liver disease (MAFLD) is fundamentally driven by an imbalance in hepatic fatty-acid flux: the influx of fatty acids exceeds the liver’s capacity for disposal, resulting in excessive hepatic lipid accumulation, predominantly in the form of triglycerides (TGs). The occurrence and progression of MAFLD depend on disordered regulation across multiple metabolic steps, including fatty-acid uptake, de novo lipogenesis (DNL), fatty-acid oxidation (FAO), and very low-density lipoprotein (VLDL) export. Forkhead box protein O1 (FOXO1) is a key transcriptional regulator within the hepatic network coordinating glucose and lipid metabolism. Under metabolic stress and insulin resistance (IR), FOXO1 expression is frequently increased, whereas its inhibitory phosphorylation is reduced. These changes enhance FOXO1 nuclear localization and transcriptional activity, thereby reprogramming the expression of genes related to metabolism in the liver. Because hepatic lipid deposition is the central pathological feature of MAFLD, the functional status of FOXO1 directly influences hepatic lipid homeostasis. Growing evidence suggests that FOXO1 can exert bidirectional, environment-dependent effects on hepatic lipid accumulation; however, the molecular basis for this functional switch remains incompletely understood. This review systematically summarizes the biological functions and regulatory mechanisms of FOXO1 and its roles in hepatic lipid metabolism, with a particular focus on its crosstalk with insulin signaling. FOXO1 expression is shaped by RNA modifications and epigenetic regulation mediated by non-coding RNAs. Its transcriptional output is precisely governed by post-translational modifications—such as phosphorylation and acetylation—as well as by coordinated nucleocytoplasmic shuttling. Notably, these regulatory patterns vary markedly across nutritional states, degrees of insulin resistance, and stages of disease. In the fed state, insulin/IGF-1 signaling activates the PI3K-AKT pathway, promoting the inhibitory phosphorylation of FOXO1 and facilitating additional modifications, including acetylation, methylation, and ubiquitination. Together, these events drive FOXO1 export from the nucleus and dampen its transcriptional activity, suppressing gluconeogenesis and constraining lipogenic programs. Conversely, during fasting or when insulin signaling is weakened, FOXO1 inhibition is relieved. FOXO1 accumulates in the nucleus, binds to DNA, and regulates the transcription of downstream target genes. Mechanistically, FOXO1 can aggravate hepatic lipid accumulation by activating genes involved in TG synthesis while repressing FAO-related pathways, thereby favoring storage over oxidation. However, under specific conditions, FOXO1 may also alleviate the hepatic lipid burden by promoting TG hydrolysis and enhancing VLDL secretion, thereby reducing the net hepatic lipid load. In addition, lipotoxic signals mediated by ceramides and diacylglycerols (Cer/DAG) activate atypical protein kinase C (aPKC), further exacerbating the disruption of the AKT-FOXO1 axis. This vicious cycle ultimately produces a metabolic paradox in which increased hepatic glucose output coexists with persistent, insulin-independent lipogenesis, accelerating MAFLD progression. Importantly, FOXO1 regulation is not uniform: during early metabolic overload, insulin-mediated suppression may remain effective, whereas in advanced insulin resistance, the loss of AKT control permits sustained FOXO1 activity. Such stage-dependent dynamics may help explain why FOXO1 can either promote steatosis or, in certain contexts, support programs that facilitate lipid turnover. Accordingly, interventions should be liver-specific and tuned to the disease stage, aiming to curb maladaptive FOXO1 signaling while preserving its capacity to promote triglyceride hydrolysis and VLDL secretion when advantageous. Overall, this review offers an important perspective on MAFLD pathogenesis, emphasizing FOXO1 as a potential therapeutic target and providing a theoretical basis for developing liver-specific, disease-course-dependent precision interventions.


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