Endocrine System Research Articles

Thyroid Papillary Carcinoma Invasion of the Ipsilateral Internal Jugular Vein: A Case Report

Thyroid cancer is the common malignancy of the endocrine system. Thyroid neoplasms are usually asymptomatic and slow growing. Uncommonly, aggressive thyroid neoplasms may invade adjacent blood vessels. Internal jugular vein invasion is a rare complication of an aggressive thyroid malignancy. Careful sonographic examination of a thrombus-like structure inside a blood vessel adjacent to the affected thyroid could reveal that the “thrombus” is part of the thyroid mass. The continuity of a thyroid neoplasm into the vascular lumen and inner-“thrombus” vascularity confirms the cancerous invasion. Ultrasound-guided fine-needle aspiration biopsy is standard for differentiating benign versus malignant thyroid nodules. Genetic testing of thyroid nodules provides valuable clinical information in addition to the routine cytological analysis.

Long-term exposure of endangered Danube sturgeon (Acipenser gueldenstaedtii) to bisphenol A (BPA): growth, behavioral, histological, genotoxic, and hematological evaluation.

Danube sturgeon (Acipenser gueldenstaedtii) which is identified as endangered species can be exposed to pollutants such as bisphenol A (BPA) that have a disruptive effect on the endocrine system at any time. Starting from this motivation, the current study focused on BPA toxicity in A. gueldenstaedtii juvenile individuals and its adverse effects in sub-lethal concentration. The median lethal concentration (LC50) of BPA was 5.03mg/L in 96th hour. In the chronic period, 0.625mg/L and 1.25mg/L BPA concentrations were evaluated based on the result of acute study. Accordingly, growth performance was significantly decreased in BPA groups (1.25mg/L BPA group was significantly lowest) compared to control (p < 0.05). In the acute period, behavioral disorders were standing at the bottom/corner of tank, slowing and stopping of gill movement, decreased response to stimuli, and death, respectively. While vacuolization was severe in the liver tissue of the fish in the acute period, intense necrosis and melanomacrophage centers were observed in the chronic period. In terms of genotoxicity, longer DNA migration was observed in all groups exposed to BPA than in the control group. In addition, lower erythrocyte and hemoglobin were observed in the BPA groups compared to control. As a result, the current study revealed toxic effect of BPA on A. gueldenstaedtii juvenile individuals and its negative results on fish physiology.

Repeated-dose toxicity and toxicokinetic study of isobutylparaben in rats subcutaneously treated for 13weeks.

Parabens have historically served as antimicrobial preservatives in a range of consumables such as food, beverages, medications, and personal care products due to their broad-spectrum antibacterial and antifungal properties. Traditionally, these compounds were believed to exhibit low toxicity, causing minimal irritation, and possessing limited sensitization potential. However, recent evidence suggests that parabens might function as endocrine-disrupting chemicals (EDCs). Consequently, extensive research is underway to elucidate potential human health implications arising from exposure to these substances. Among these parabens, particular concerns have been raised regarding the potential adverse effects of iso-butylparaben (IBP). Studies have specifically highlighted its potential for inducing hormonal disruption, significant ocular damage, and allergic skin reactions. This study aimed to evaluate the prolonged systemic toxicity, semen quality, and estrus cycle in relation to endocrine disruption endpoints, alongside assessing the toxicokinetic behavior of IBP in Sprague-Dawley rats following a 13-week repeated subcutaneous administration. The rats were administered either the vehicle (4% Tween 80) or IBP at dosage levels of 2, 10, and 50mg/kg/day for 13weeks. Blood collection for toxicokinetic study was conducted on three specified days: day 1 (1st), day 30 (2nd), and day 91 (3rd). Systemic toxicity assessment and potential endocrine effects were based on various parameters including mortality rates, clinical signs, body weights, food and water consumption, ophthalmological findings, urinalysis, hematological and clinical biochemistry tests, organ weights, necropsy and histopathological findings, estrus cycle regularity, semen quality, and toxicokinetic behavior. The findings revealed that IBP induced local irritation at the injection site in males at doses ≥ 10mg/kg/day and in females at 50mg/kg/day; however, systemic toxicity was not observed. Consequently, the no-observed-adverse-effect level (NOAEL) for IBP was determined to be 50mg/kg/day in rats of both sexes, indicating no impact on the endocrine system. The toxicokinetics of IBP exhibited dose-dependent systemic exposure, reaching a maximum dose of 50mg/kg/day, and repeated administration over 13weeks showed no signs of accumulation.

The role of the brain renin-angiotensin system in Parkinson´s disease.

The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.

Do Parental Hormone Levels Synchronize During the Prenatal and Postpartum Periods? A Systematic Review.

Physiological synchrony is the phenomenon of linked physiological processes among two or more individuals. Evidence of linkage between dyads has been found among a broad range of physiological indices, including the endocrine systems. During the transition to parenthood, both men and women undergo hormonal changes that facilitate parenting behavior. The present review sought to address the question as to whether hormonal synchronization occurs among expecting or new parents. A systematic literature search yielded 13 eligible records. The evidence of cortisol synchrony during the prenatal period, with additional testosterone, prolactin, and progesterone covariations in the time leading up to childbirth, was found to be most significant. During the postpartum period, parental synchrony was reported for oxytocin, testosterone, and cortisol levels. The implications of these covariations were found to translate into adaptive parenting behaviors and the facilitation of romantic bond. Associations with infant development were also reported, suggesting far-reaching effects of hormonal synchrony outside the parental dyad. The results highlight the importance of physiological interrelatedness during this sensitive period, underscoring the need for further research in this field. In view of the limited data available in this research domain, we have put forward a framework for future studies, recommending the adoption of standardized research protocols and repeated collections of specimens.

Vitamin D and Dyslipidemia: Is There Really a Link? A Narrative Review

Nowadays, the interest in the extraskeletal effects of vitamin D is growing. In the literature, its several possible actions have been confirmed. Vitamin D seems to have a regulatory role in many different fields—inflammation, immunity, and the endocrine system—and many studies would demonstrate a possible correlation between vitamin D and cardiovascular disease. In this paper, we deepened the relationship between vitamin D and dyslipidemia by reviewing the available literature. The results are not entirely clear-cut: on the one hand, numerous observational studies suggest a link between higher serum vitamin D levels and a beneficial lipid profile, while on the other hand, interventional studies do not demonstrate a significant effect. Understanding the possible relationship between vitamin D and dyslipidemia may represent a turning point: another link between vitamin D and the cardiovascular system.

CAPN2 correlates with insulin resistance states in PCOS as evidenced by multi-dataset analysis

ObjectiveIR emerges as a feature in the pathophysiology of PCOS, precipitating ovulatory anomalies and endometrial dysfunctions that contribute to the infertility challenges characteristic of this condition. Despite its clinical significance, a consensus on the precise mechanisms by which IR exacerbates PCOS is still lacking. This study aims to harness bioinformatics tools to unearth key IR-associated genes in PCOS patients, providing a platform for future therapeutic research and potential intervention strategies.MethodsWe retrieved 4 datasets detailing PCOS from the GEO, and sourced IRGs from the MSigDB. We applied WGCNA to identify gene modules linked to insulin resistance, utilizing IR scores as a phenotypic marker. Gene refinement was executed through the LASSO, SVM, and Boruta feature selection algorithms. qPCR was carried out on selected samples to confirm findings. We predicted both miRNA and lncRNA targets using the ENCORI database, which facilitated the construction of a ceRNA network. Lastly, a drug-target network was derived from the CTD.ResultsThirteen genes related to insulin resistance in PCOS were identified via WGCNA analysis. LASSO, SVM, and Boruta algorithms further isolated CAPN2 as a notably upregulated gene, corroborated by biological verification. The ceRNA network involving lncRNA XIST and hsa-miR-433-3p indicated a possible regulatory link with CAPN2, supported by ENCORI database. Drug prediction analysis uncovered seven pharmacological agents, most being significant regulators of the endocrine system, as potential candidates for addressing insulin resistance in PCOS.ConclusionsThis study highlights the pivotal role of CAPN2 in insulin resistance within the context of PCOS, emphasizing its importance as both a critical biomarker and a potential therapeutic target. By identifying CAPN2, our research contributes to the expanding evidence surrounding the CAPN family, particularly CAPN10, in insulin resistance studies beyond PCOS. This work enriches our understanding of the mechanisms underlying insulin resistance, offering insights that bridge gaps in the current scientific landscape.

Enhanced identification of endocrine disruptors through integration of science-based regulatory practices and innovative methodologies: The MERLON Project

The prevalence of hormone-related health issues caused by exposure to endocrine disrupting chemicals (EDCs) is a significant, and increasing, societal challenge. Declining fertility rates together with rising incidence rates of reproductive disorders and other endocrine-related diseases underscores the urgency in taking more action. Addressing the growing threat of EDCs in our environment demands robust and reliable test methods to assess a broad variety of endpoints relevant for endocrine disruption. EDCs also require effective regulatory frameworks, especially as the current move towards greater reliance on non-animal methods in chemical testing puts to test the current paradigm for EDC identification, which requires that an adverse effect is observed in an intact organism. Although great advances have been made in the field of predictive toxicology, disruption to the endocrine system and subsequent adverse health effects may prove particularly difficult to predict without traditional animal models. The MERLON project seeks to expedite progress by integrating multispecies molecular research, new approach methodologies (NAMs), human clinical epidemiology, and systems biology to furnish mechanistic insights and explore ways forward for NAM-based identification of EDCs. The focus is on sexual development and function, from foetal sex differentiation of the reproductive system through mini-puberty and puberty to sexual maturity. The project aims are geared towards closing existing knowledge gaps in understanding the effects of EDCs on human health to ultimately support effective regulation of EDCs in the European Union and beyond.

Molecular strategies of the pygmy grasshopper Eucriotettix oculatus adapting to long-term heavy metal pollution

To study the heavy metal accumulation and its impact on insect exterior and chromosome morphology, and reveal the molecular mechanism of insects adapting to long-term heavy metal compound pollution habitats, this study, in the Diaojiang river basin, which has been polluted by heavy metals(HMs) for nearly a thousand years, two Eucriotettix oculatus populations was collected from mining and non-mining areas. It was found that the contents of 7 heavy metals (As, Cd, Pb, Zn, Cu, Sn, Sb) in E. oculatus of the mining area were higher than that in the non-mining 1–11 times. The analysis of morphology shows that the external morphology, the hind wing type and the chromosomal morphology of E. oculatus are significant differences between the two populations. Based on the heavy metal accumulation，morphological change, and stable population density, it is inferred that the mining area population has been affected by heavy metals and has adapted to the environment of heavy metals pollution. Then, by analyzing the transcriptome of the two populations, it was found that the digestion, immunity, excretion, endocrine, nerve, circulation, reproductive and other systems and lysosomes, endoplasmic reticulum and other cell structure-related gene expression were suppressed. This shows that the functions of the above-mentioned related systems of E. oculatus are inhibited by heavy metal stress. However, it has also been found that through the significant up-regulation of genes related to the above system, such as ATP2B, pepsin A, ubiquitin, AQP1, ACOX, ATPeV0A, SEC61A, CANX, ALDH7A1, DLD, aceE, Hsp40, and catalase, etc., and the down-regulation of MAPK signalling pathway genes, can enhanced nutrient absorption, improve energy metabolism, repair damaged cells and degrade abnormal proteins, maintain the stability of cells and systems, and resist heavy metal damage so that E. oculatus can adapt to the environment of heavy metal pollution for a long time.

Glyphosate: Hepatotoxicity, Nephrotoxicity, Hemotoxicity, Carcinogenicity, and Clinical Cases of Endocrine, Reproductive, Cardiovascular, and Pulmonary System Intoxication

Glyphosate: Hepatotoxicity, Nephrotoxicity, Hemotoxicity, Carcinogenicity, and Clinical Cases of Endocrine, Reproductive, Cardiovascular, and Pulmonary System Intoxication

Pollution profile by n-alkanes in sediment and surface water of the Paranaguá Estuarine Complex

The increase in urban demand derived from human activities has contributed to pollution levels in water environments, compromising the quality of water, sediments, and aquatic biota. Estuarine environments receive multiple influences from anthropogenic activities that contribute to the deposition of organic pollutants in the environment, including n-alkanes. In this context, n-alkanes are hydrocarbons that can be found in the environment through natural ecosystem activities as well as through pollution by human practices. Due to their degradation resistance characteristics, they are considered good markers of environmental pollution. The presence of hydrocarbons in the environment can become a major stressor in the environment, being associated with cases of cancer, mutations, and changes in the endocrine system of animals and humans. This study aimed to evaluate the pollution profile of surface water and sediments caused by the presence of n-alkanes. For this, it was evaluated the presence of n-alkanes in surface water and sediment at ten points in the Paranaguá Estuarine Complex (Paraná – Brazil), comprising areas influenced by the sea and part of an urbanized river, during four distinct events. The concentrations in water reached a maximum value of 61.7 µg L-1, while in the sediment, the value was 8825.09 µg Kg-1. The diagnostic reasons suggest mixed sources of contribution, but reaffirm the portion of anthropic contribution to estuarine pollution and reinforce the pressures of human activities in processes of degradation of water bodies. It is expected that the data found will serve as a basis for future work and support decision-making in the context of water resources management in the region.

Epigenetic Responses to Nonchemical Stressors: Potential Molecular Links to Perinatal Health Outcomes.

We summarize the recent literature investigating exposure to four nonchemical stressors (financial stress, racism, psychosocial stress, and trauma) and DNA methylation, miRNA expression, and mRNA expression. We also highlight the relationships between these epigenetic changes and six critical perinatal outcomes (preterm birth, low birth weight, preeclampsia, gestational diabetes, childhood allergic disease, and childhood neurocognition). Multiple studies have found financial stress, psychosocial stress, and trauma to be associated with DNA methylation and/or miRNA and mRNA expression. Fewer studies have investigated the effects of racism. The majority of studies assessed epigenetic or genomic changes in maternal blood, cord blood, or placenta. Several studies included multi-OMIC assessments in which DNA methylation and/or miRNA expression were associated with gene expression. There is strong evidence for the role of epigenetics in driving the health outcomes considered. A total of 22 biomarkers, including numerous HPA axis genes, were identified to be epigenetically altered by both stressors and outcomes. Epigenetic changes related to inflammation, the immune and endocrine systems, and cell growth and survival were highlighted across numerous studies. Maternal exposure to nonchemical stressors is associated with epigenetic and/or genomic changes in a tissue-specific manner among inflammatory, immune, endocrine, and cell growth-related pathways, which may act as mediating pathways to perinatal health outcomes. Future research can test the mediating role of the specific biomarkers identified as linked with both stressors and outcomes. Understanding underlying epigenetic mechanisms altered by nonchemical stressors can provide a better understanding of how chemical and nonchemical exposures interact.

Adipose tissue plasticity mediated by the counterregulatory axis of the renin-angiotensin system: Role of Mas and MrgD receptors.

The renin-angiotensin system (RAS) is an endocrine system composed of two main axes: the classical and the counterregulatory, very often displaying opposing effects. The classical axis, primarily mediated by angiotensin receptors type 1 (AT1R), is linked to obesity-associated metabolic effects. On the other hand, the counterregulatory axis appears to exert antiobesity effects through the activation of two receptors, the G protein-coupled receptor (MasR) and Mas-related receptor type D (MrgD). The local RAS in adipose organ has prompted extensive research into white adipose tissue and brown adipose tissue (BAT), with a key role in regulating the cellular and metabolic plasticity of these tissues. The MasR activation favors the brown plasticity signature in the adipose organ by improve the thermogenesis, adipogenesis, and lipolysis, decrease the inflammatory state, and overall energy homeostasis. The MrgD metabolic effects are related to the maintenance of BAT functionality, but the signaling remains unexplored. This review provides a summary of RAS counterregulatory actions triggered by Mas and MrgD receptors on adipose tissue plasticity. Focus on the effects related to the morphology and function of adipose tissue, especially from animal studies, will be given targeting new avenues for treatment of obesity-associated metabolic effects.

Current progresses and challenges for microbiome research in human health: a perspective

It is becoming increasingly clear that the human microbiota, also known as “the hidden organ”, possesses a pivotal role in numerous processes involved in maintaining the physiological functions of the host, such as nutrient extraction, biosynthesis of bioactive molecules, interplay with the immune, endocrine, and nervous systems, as well as resistance to the colonization of potential invading pathogens. In the last decade, the development of metagenomic approaches based on the sequencing of the bacterial 16s rRNA gene via Next Generation Sequencing, followed by whole genome sequencing via third generation sequencing technologies, has been one of the great advances in molecular biology, allowing a better profiling of the human microbiota composition and, hence, a deeper understanding of the importance of microbiota in the etiopathogenesis of different pathologies. In this scenario, it is of the utmost importance to comprehensively characterize the human microbiota in relation to disease pathogenesis, in order to develop novel potential treatment or preventive strategies by manipulating the microbiota. Therefore, this perspective will focus on the progress, challenges, and promises of the current and future technological approaches for microbiome profiling and analysis.

Asprosin: its function as a novel endocrine factor in metabolic-related diseases.

Asprosin was discovered as a new endocrine hormone originating from fibrillin-1 cleavage that plays a crucial role in various metabolic-related diseases, such as obesity, nonalcoholic fatty liver disease (NAFLD), diabetes, polycystic ovary syndrome (PCOS), and cardiovascular diseases. The purpose of this review is to describe the recent advancements of asprosin. Narrative review. This comprehensive review explores its tissue-specific functions, focusing on white adipose tissue, liver, hypothalamus, testis, ovary, heart, pancreas, skeletal muscle, and kidney. Asprosin is a multifaceted protein with tissue-specific roles in various physiological and pathological processes. Further research is needed to fully understand the mechanisms and potential of asprosin as a therapeutic target. These insights could provide new directions for treatments targeting metabolic-related diseases.

The gut microbiome and sociability

The human gut microbiome plays an important role in the maturation of the neural, immune, and endocrine systems. Research data from animal models shows that gut microbiota communicate with the host's brain in an elaborate network of signaling pathways, including the vagus nerve. Part of the microbiome's influence extends to the behavioral and social development of its host. As a social species, a human's ability to communicate with others is imperative to their survival and quality of life. Current research explores the gut microbiota's developmental influence as well as how these gut-brain pathways can be leveraged to alleviate the social symptoms associated with various neurodevelopmental and psychiatric diseases. One intriguing vein of research in animal models centers on probiotic treatment, which leads to downstream increased circulation of endogenous oxytocin, a neuropeptide hormone relevant to sociability. Further research may lead to therapeutic applications in humans, particularly in the early stages of their lives.

Therapeutic Potential of the Linalool against Cadmium-Induced Testicular Tissue Damage

Cadmium (Cd) is a heavy metal that has harmful effects and is one of the contaminants found in the environment. Cd exposure causes important pathophysiological processes, such as reproductive toxicity. Linalool (Lnl) is a monoterpene, a component of essential oils known to be produced synthetically. Additionally, Lnl has many important beneficial effects, such as anti-inflammatory and antioxidant effects. The objective of this study is to determine whether Lnl has a healing impact in opposition to testicular tissue damage due to Cd exposure. In the study, 28 male rats were divided at random into four equal groups (n = 7). No treatment was applied to the control group. CdCl2 was applied intraperitoneally to the Cd group at a dose of 3mg/kg for the first 7 days of the trial. For the Cd+Lnl group, 3mg/kg CdCl2 was applied intraperitoneally for the first 7 days of the trial, and 100mg/kg/day Lnl was applied. Upon completion of all applications, the rats were sacrificed and blood samples and testicular tissue were taken. Cd exposure caused histopathological changes, oxidative stress, inflammation, and an increase in apoptotic cells in testicular tissue. However, Cd altered endocrine hormones in the hypothalamic-pituitary-gonad axis. However, Lnl application against Cd exposure was able to regulate the negativity caused by Cd in both testicular tissue and endocrine hormone levels. In conclusion, Lnl may be a potential therapeutic strategy against Cd-induced reproductive toxicity. We believe that Lnl has a high potential for further studies to determine its detailed mechanisms of action and cellular signalling pathways.

Long-term dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) reduced feeding in common carp (Cyprinus carpio): via the JAK-STAT signaling pathway

Polybrominated diphenyl ethers (PBDEs) are widely present in water ecosystems where they pose a significant threat to aquatic life, but our knowledge about how PBDEs affect feeding is limited. Therefore, this study explored the effects of continuous dietary exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) (40 and 4000 ng/g) on the feeding in common carp (Cyprinus carpio) and the underlying mechanism. BDE-47 significantly decreased the food intake of carp. Transcriptome analysis of brain tissue showed that BDE-47 mainly affected the nervous, immune, and endocrine systems. Further examination of the expression levels of appetite factors in the brain revealed that BDE-47 caused dysregulation of appetite factors expressions such as agrp, pomc, cart, etc. In addition, the JAK-STAT signaling pathway was activated under BDE-47 exposure. It can be concluded from these findings that BDE-47 activated the JAK-STAT signaling pathway, causing imbalanced expression of appetite factors, leading to disordered feeding behavior and decreased food intake in carp. These results provide an important reference for a more comprehensive understanding of the hazards posed by BDE-47 on animal feeding and the associated mechanisms.

Integrated analysis of intestinal microbiota and transcriptome reveals that a coordinated interaction of the endocrine, immune system and gut microbiota response to heat stress in Litopenaeus vannamei

Due to the ongoing global warming, the risk of heatwaves in the oceans is continuously increasing while our understanding of the physiological response of Litopenaeus vannamei under extreme temperature conditions remains limited. Therefore, this study aimed to evaluate the physiological responses of L. vannamei under heat stress. Our results indicated that as temperature rose, the structure of intestinal and hepatopancreatic tissues was damaged sequentially. Activity of immune-related enzymes (acid phosphatase/alkaline phosphatase) initially increased before decreased, while antioxidant enzymes (superoxide dismutase and glutathione-S transferase) activity and malondialdehyde content increased with rising temperature. In addition, the total antioxidant capacity decreased with rising temperature. With the rising temperature, there was a significant increase in the expression of caspase-3, heat shock protein 70, lipopolysaccharide-induced tumor necrosis factor-α, transcriptional enhanced associate domain and yorkie in intestinal and hepatopancreatic tissues. Following heat stress, the number of potentially beneficial bacteria (Rhodobacteraceae and Gemmonbacter) increased which maintain balance and promote vitamin synthesis. Intestinal transcriptome analysis revealed 852 differentially expressed genes in the heat stress group compared with the control group. KEGG functional annotation results showed that the endocrine system was the most abundant in Organismal systems followed by the immune system. These results indicated that heat stress leads to tissue damage in shrimp, however the shrimp may respond to stress through a coordinated interaction strategy of the endocrine system, immune system and gut microbiota. This study revealed the response mechanism of L. vannamei to acute heat stress and potentially provided a theoretical foundation for future research on shrimp environmental adaptations.

Mesenchymal stem/stromal cells armored by FGF21 ameliorate alcohol-induced liver injury through modulating polarization of macrophages.

Alcohol-associated liver disease (ALD) is a major health care challenge worldwide with limited therapeutic options. Although mesenchymal stem/stromal cells (MSCs) represent a newly emerging therapeutic approach to treat ALD, thus far, there have been extensive efforts to try and enhance their efficacy, including genetically engineering MSCs. FGF21, an endocrine stress-responsive hormone, has been shown to regulate energy balance, glucose, and lipid metabolism and to enhance the homing of MSCs toward injured sites. Therefore, the purpose of this study was to investigate whether MSCs that overexpress FGF21 (FGF21-MSCs) improve the therapeutic effect of MSCs in treating ALD. Human umbilical cord-derived MSCs served as the gene delivery vehicle for the FGF21 gene. Human umbilical cord-derived MSCs were transduced with the FGF21 gene using lentiviral vectors to mediate FGF21 overexpression. We utilized both chronic Lieber-DeCarli and Gao-binge models of ethanol-induced liver injury to observe the therapeutic effect of FGF21-MSCs. Liver injury was phenotypically evaluated by performing biochemical methods, histology, and inflammatory cytokine levels. Compared with MSCs alone, administration of MSCs overexpressing FGF21(FGF21-MSCs) treatment significantly enhanced the therapeutic effect of ALD in mice, as indicated by the alleviation of liver injury with reduced steatosis, inflammatory infiltration, oxidative stress, and hepatic apoptosis, and the promotion of liver regeneration. Mechanistically, FGF21 could facilitate the immunomodulatory function of MSCs on macrophages by setting metabolic commitment for oxidative phosphorylation, which enables macrophages to exhibit anti-inflammatory inclination. Our data elucidate that MSC modification by FGF21 could enhance their therapeutic effect in ALD and may help in the exploration of effective MSCs-based cell therapies for the treatment of ALD.