Impact of cytokine storm and systemic inflammation on liver impairment patients infected by SARS-CoV-2:Prospective therapeutic challenges

Coronavirus disease 2019(COVID-19)is a devastating worldwide pandemic infection caused by a severe acute respiratory syndrome namely coronavirus 2(SARS-CoV-2)that is associated with a high spreading and mortality rate.On the date this review was written,SARS-CoV-2 infected about 96 million people and killed about 2 million people.Several arguments disclosed the high mortality of COVID-19 due to acute respiratory distress syndrome or change in the amount of angiotensin-converting enzyme 2(ACE2)receptor expression or cytokine storm strength production.In a similar pattern,hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming,which worsens the hepatic impairment and increases the mortality rate.In this review,the impact of SARS-CoV-2 on hepatic impairment conditions we overviewed.Besides,we focused on the recent studies that indicated cytokine storm as well as ACE2 as the main factors for high COVID-19 spreading and mortality while hinting at the potential therapeutic strategies.

Mesenchymal stem/stromal cells as adjuvant therapy in COVID-19- associated acute lung injury and cytokine storm: Importance of cell identification

Theoretically, mesenchymal stem cells (MSCs) are very promising as adjuvanttherapy to alleviate coronavirus disease 2019 (COVID-19)-associated acute lunginjury and cytokine storm. Several published studies, which used MSCs toalleviate COVID-19-associated acute lung injury and cytokine storm, reportedpromising results. However, the evidence came from a case report, case series,and clinical trials with a limited number of participants. Therefore, more studiesare needed to get robust proof of MSC beneficial effects.

Liver dysfunction as a cytokine storm manifestation and prognostic factor for severe COVID-19

patients with or without preexisting liver disorders,posing a significant complication and mortality risk.During coronavirus disease 2019(COVID-19),abnormal liver function is typically observed.However,liver injury may occur because of the treatment as well.Ischemia,cytokine storm,and hypoxia were identified as the three major factors contributing to liver damage during COVID-19.Indeed,raised liver enzymes during hospitalizations may be attributed to medications used,as well as sepsis and shock.As a result,the proportion of hospitalized patients afflicted with COVID-19 and pathological liver biomarkers varies from 14%to 53%.Aminotransferases and bilirubin are found most often elevated.Usually,increased gamma-glutamyltransferase,alkaline phosphatase,and decreased serum albumin levels are demonstrated.Additionally,although there is no specific treatment for COVID-19,many of the drugs used to treat the infection are hepatotoxic.In this mini-review,we focus on how liver dysfunction can be one of the features associated with the COVID-19 cytokine storm.Furthermore,data show that liver injury can be an independent predictor of severe COVID-19,the need for hospitalization,and death.

Network pharmacological study of Qingfei Paidu Decoction intervening on cytokine storm mechanism of COVID-19

Objective:To explore the possible mechanism of Qingfei Paibu Decoction in the treatment of COVID-19 from the perspective of cytokine storm by network pharmacology.Methods: The TCMSP and SymMap databases were used to screen out the active components and targets of Qingfei Paibu Decoction;The GeneCards database was used to screen the predicted targets of COVID-19;Two targets were mapped;The STRING database and Cytoscape3.7.2 software were used to construct the network diagram of active drag-ingredient-target and screen out the core components and targets;The GO enrichment analysis and KEGG pathway enrichment analysis were carried out by OmicShare cloud platform and David respectively.Results:A total of 52 potential targets of Qingfei Paibu Decoction for the treatment of COVID-19 were obtained, among which 17 were core targets related to inflammation, mainly including cytokines such as IL, IFN, TNF and chemokines. And 26 core components were obtained, including quercetin, luteolin, kaempferol, naringenin, and baicalein;The GO enrichment results showed 224 biological processes, 15 molecular functions and 33 cell components related to inflammation;There were 5 inflammatory signaling pathways in KEGG enrichment results, including TNF signaling pathway, Nod-like receptor signaling pathway, Toll-like receptor signaling pathway, MAPK signaling pathway and cytokine receptor interaction. Conclusion: Qingfei Paibu Decoction can inhibit cytokine storms by acting on multiple targets and pathways with multiple components and thus treat COVID-19.

May mesenchymal stem cell transplantation be a solution for COVID-19 induced cytokine storm?

The recently emergent disease caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),transmitted by droplets and aerosols,was named coronavirus disease 2019(COVID-19)by World Health Organization.Predominantly,the disease progress is asymptomatic or mild,but one-fifth of the patients advance to severe or critical illness.In severe COVID-19 patients,type-2 T helper cells release numerous cytokines;this excessive immune response is named as cytokine storm.The cytokine storm,which is the hallmark of the COVID-19 induced by the disease and aggravates due to lack of proper immune response,similar to SARS and Middle East respiratory syndrome(MERS),and the disease status may progress forward to acute respiratory distress syndrome(ARDS),systemic inflammatory response syndrome,multi-organ dysfunction syndrome,and death.Mesenchymal stromal cell transplantation is up-and-coming in treating many diseases such as HIV,hepatitis B,influenza,coronavirus diseases(SARS,MERS),lung injuries,and ARDS.Upon closer inspection on respiratory diseases,COVID-19,influenza,SARS,and MERS have similarities in patho-genesis,especially cytokine and immune response profiles.These comparable features in terms of the cytokine storm will provide hints for the treatment of COVID-19.

SARS-CoV-2-the Unforeseen Peril of David Winning Against Goliath:the Immune Giant Collapsing Under Its Own Rampaging Cytokine Storm

We examined SARS-CoV-2(Covid-19)available treatments and prophylactic methods that included interventions associated with inhibiting the“type II transmembrane serine protease”(TMPRSS2)to limit the fusion between the Covid-19 Spike proteins and ACE2 receptors,or newly developed therapeutics like Remdesivir that interferes with the viral RNA replication.We explored the dilemma of ACE2 receptors that have a protective function against high blood pressure associated disorders,yet,they serve as the viral points of entry,elevating the probability of infection.Human tissues’analysis reveals a higher ACE2 expression in adipose tissue,placing obesity-related conditions in the eye of the pandemic storm.It primarily exposes males due to the surge of ACE2 receptors in the testes along with other tissues.Males manifest a relatively higher positive ACE2 correlations with certain immune cells in the lungs,thyroid,adrenals,liver and colon,while females evidence higher ACE2 correlations with immune cells in the heart.The remaining tissues’ACE2/immunity expressions are equivalent in both sexes,indicating that despite its preference for males,the threat of Covid-19 can easily target females.Recent reports indicate that Covid-19 is empowered by hindering the critical process of viral recognition during the adaptive immune response leading to the“cytokine storm”,the aggravated immune response that indiscriminately perseveres,rampaging the host’s vital organs.Sedentary lifestyle,age-related hormonal imbalance,and adiposity induced inflammation predispose the body to the immune collapse following Covid-19 invasion,spotlighting the detrimental aftermath of metabolic dysfunction,and excess food consumption provoked by elevated cortisol and dysregulated appetite hormones.ACE 2 expression is suppressed in the skeletal muscle,rendering fitness and weight management an effective Covid-19 preventive intervention,along with social distancing,hygiene,and facial coverings.Physical activity,or exercise alternative methods have recently demonstrated statistically significant reductions of the inflammatory marker C-Reactive Protein(CRP),triglycerides,visceral fat,cortisol and the orexigenic hormone ghrelin,juxtaposed by optimal increases of IGF-1,skeletal muscle mass,Free T3,HDL,and the anorexic hormone leptin.

Regulation of cytokine storm by marine traditional Chinese medicine

At present,COVID-19 is outbreaking worldwide,and the severity of the disease is closely related to the intensity of cytokine storm and inflammatory response.Cytokine storm is an excessive immune response to external stimuli,with complex pathogenesis and high mortality.In the New Coronavirus Infected Pneumonia Diagnosis and Treatment Program,a variety of measures are recommended for treatment,such as respiratory support,circulatory support,glucocorticoids and traditional Chinese medicine prescriptions to suppress the cytokine storm in the late clinical stage.At present,the combination of traditional Chinese medicine and Western medicine has achieved good results in clinical practice.Traditional Chinese medicine has contributed greatly to human health and world civilization,and is also a characteristic health resource in China.It has been adhering to the principle of"treating the symptoms at the time and treating the root cause in ordinary time",and has shown obvious efficacy in a variety of immune diseases.Ocean occupies 70%of the earth's surface,which contains abundant resources of traditional Chinese medicine.This paper analyzed the effect of marine algae traditional Chinese medicine on cytokine storm and immune regulation,hoping to provide a supplement to the existing application of traditional Chinese medicine,and provide some references for the development of drugs to inhibit cytokine storm from the sea.

Clinical Manifestations of Cytokine Storm and Immune Response to COVID-19: Literature Review

Spreading COVID-19 disease caused by coronavirus 2 causes tremendous health challenges worldwide. Owing to a high transmission rate, fast-spreading disease, asymptomatic carriers, and high infectivity, we observe a pandemic status that we follow today. Although there are different reports of case fatality rates around the globe, the primary determinant of mortality is age. Symptoms of COVID-19 disease vary from asymptomatic individuals to severe acute respiratory distress syndrome (ARDS) and death. The most common complication of COVID-19 is ARDS. Hyperinflammation due to excessive immune response to coronavirus is the leading cause of severe symptoms seen in the course of COVID-19. The virus enters cells utilizing the S1 subunit through the ACE2 receptor. The innate immune response is the primary immune reaction to virus entry. RNA viruses, including corona-virus, replicate in the cytoplasm, assemble, and then exit by exocytosis. Some suggest that SARS-Cov2 uses cell-cell fusion to infect adjacent cells. Different sensors detect the virus particles in the endosomal compartment and cytoplasm, and infected cells induce an immune response to surrounding cells. As a result, the production of cytokines and chemokines such as interferons (INFs) will be augmented. Since coronavirus uses different means to evade the immune system, it is difficult for immune cells to “sense” them;thus, the coronavirus response is not adequate. It has been showing that even a sufficient level of immunoglobulin response couldn’t neutralize virus replication. Therefore, the innate immune response is unable to eradicate SARS-Cov2, causes overexpression of cytokines and chemokines that cannot eliminate the virus. Diminished INFs secretion and apoptosis of regulatory T cells (Treg) are the leading cause of dysregulated immune response in a cytokine storm. Inflammatory cells attack infected and uninfected cells, causing more inflammation and apoptosis of endothelial and epithelial cells. In the end, organ failure occurs due to immune cells’ overactivity, cell proliferation, hemorrhage, microthrombi, and remodeling of tissue cells. This review discusses the immune response and pathomechanisms of the associated symptoms in COVID-19.

Cytokine nanosponges suppressing overactive macrophages and dampening systematic cytokine storm for the treatment of hemophagocytic lymphohistiocytosis

Hemophagocytic lymphohistiocytosis(HLH)is a highly fatal condition with the positive feedback loop between continued immune cell activation and cytokine storm as the core mechanism to mediate multiple organ dysfunction.Inspired by macrophage membranes harbor the receptors with special high affinity for proin-flammation cytokines,lipopolysaccharide(LPS)-stimulated macrophage membrane-coated nanoparticles(LMNP)were developed to show strong sponge ability to both IFN-γand IL-6 and suppressed overactivation of macrophages by inhibiting JAK/STAT signaling pathway both in vitro and in vivo.Besides,LMNP also efficiently alleviated HLH-related symptoms including cytopenia,hepatosplenomegaly and hepatorenal dysfunction and save the life of mouse models.Furthermore,its sponge effect also worked well for five human HLH samples in vitro.Altogether,it’s firstly demonstrated that biocompatible LMNP could dampen HLH with high potential for clinical transformation,which also provided alternative insights for the treatment of other cytokine storm-mediated pathologic conditions such as COVID-19 infection and cytokine releasing syndrome during CAR-T therapy.

Cytokine storm and translating IL-6 biology into effective treatments for CoVID-19

As of May 3,2023,the Coronavirus disease 2019(COVID-19)pandemic has resulted in more than 760 million confirmed cases and over 6.9 million deaths.Several patients have developed pneumonia,which can deteriorate into acute respiratory distress syndrome.The primary etiology may be attributed to cytokine storm,which is triggered by the excessive release of proinflammatory cytokines and subsequently leads to immune dysregulation.Considering that high levels of interleukin-6(IL-6)have been detected in several highly pathogenic coronavirus-infected diseases,such as severe acute respiratory syndrome in 2002,the Middle East respiratory syndrome in 2012,and COVID-19,the IL-6 pathway has emerged as a key in the pathogenesis of this hyperinflammatory state.Thus,we review the history of cytokine storm and the process of targeting IL-6 signaling to elucidate the pivotal role played by tocilizumab in combating COVID-19.

The unique ORF8 protein from SARS-CoV-2 binds to human dendritic cells and induces a hyper-inflammatory cytokine storm

The novel coronavirus pandemic,first reported in December 2019,was caused by the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection leads to a strong immune response and activation of antigen-presenting cells,which can elicit acute respiratory distress syndrome(ARDS)characterized by the rapid onset of widespread inflammation,the so-called cytokine storm.In response to viral infections,monocytes are recruited into the lung and subsequently differentiate into dendritic cells(DCs).DCs are critical players in the development of acute lung inflammation that causes ARDS.Here,we focus on the interaction of a specific SARS-CoV-2 open reading frame protein,ORF8,with DCs.We show that ORF8 binds to DCs,causes pre-maturation of differentiating DCs,and induces the secretion of multiple proinflammatory cytokines by these cells.In addition,we identified DC-SIGN as a possible interaction partner of ORF8 on DCs.Blockade of ORF8 leads to reduced production of IL-1β,IL-6,IL-12p70,TNF-α,MCP-1(also named CCL2),and IL-10 by DCs.Therefore,a neutralizing antibody blocking the ORF8-mediated cytokine and chemokine response could be an improved therapeutic strategy against SARS-CoV-2.

The cytokine storm of severe influenza and development of immunomodulatory therapy

Severe influenza remains unusual in its virulence for humans. Complications or ultimately death arising from these infections are often associated with hyperinduction of proinflammatory cytokine production, which is also known as ＇cytokine storm＇. For this disease, it has been proposed that immunomodulatory therapy may improve the outcome, with or without the combination of antiviral agents. Here, we review the current literature on how various effectors of the immune system initiate the cytokine storm and exacerbate pathological damage in hosts. We also review some of the current immunomodulatory strategies for the treatment of cytokine storms in severe influenza, including corticosteroids, peroxisome proliferator-activated receptor agonists, sphingosine-l-phosphate receptor 1 agonists, cyclooxygenase-2 inhibitors, antioxidants, anti-tumour-necrosis factor therapy, intravenous immunoglobulin therapy, statins, arbidol, herbs, and other potential therapeutic strategies.

Cytokine storm promoting T cell exhaustion in severe COVID-19 revealed by single cell sequencing data analysis

Background:Evidence has suggested that cytokine storms may be associated with T cell exhaustion(TEX)in COVID-19.However,the interaction mechanism between cytokine storms and TEX remains unclear.Methods:With the aim of dissecting the molecular relationship of cytokine storms and TEX through single-cell RNA sequencing data analysis,we identified 14 cell types from bronchoalveolar lavage fluid of COVID-19 patients and healthy people.We observed a novel subset of severely exhausted CD8 T cells(Exh T_CD8)that co-expressed multiple inhibitory receptors,and two macrophage subclasses that were the main source of cytokine storms in bronchoalveolar.Results:Correlation analysis between cytokine storm level and TEX level suggested that cytokine storms likely promoted TEX in severe COVID-19.Cell–cell communication analysis indicated that cytokines(e.g.CXCL10,CXCL11,CXCL2,CCL2,and CCL3)released by macrophages acted as ligands and significantly interacted with inhibitory receptors(e.g.CXCR3,DPP4,CCR1,CCR2,and CCR5)expressed by Exh T_CD8.These interactions formed the cytokine–receptor axes,which were also verified to be significantly correlated with cytokine storms and TEX in lung squamous cell carcinoma.Conclusions:Cytokine storms may promote TEX through cytokine-receptor axes and be associated with poor prognosis in COVID19.Blocking cytokine-receptor axes may reverse TEX.Our finding provides novel insights into TEX in COVID-19 and new clues for cytokine-targeted immunotherapy development.

Coronavirus disease 2019(COVID-19):cytokine storms,hyper-inflammatory phenotypes,and acute respiratory distress syndrome

Coronavirus Disease 2019(COVID-19)was first identified in China at the end of 2019.Acute respiratory distress syndrome(ARDS)represents the most common and serious complication of COVID-19.Cytokine storms are a pathophysiological feature of COVID-19 and play an important role in distinguishing hyper-inflammatory subphenotypes of ARDS.Accordingly,in this review,we focus on hyper-inflammatory host responses in ARDS that play a critical role in the differentiated development of COVID-19.Furthermore,we discuss inflammationrelated indicators that have the potential to identify hyper-inflammatory subphenotypes of COVID-19,especially for those with a high risk of ARDS.Finally,we explore the possibility of improving the quality of monitoring and treatment of COVID-19 patients and in reducing the incidence of critical illness and mortality via better distinguishing hyper-and hypoinflammatory subphenotypes of COVID-19.

Current remarks and future directions on the interactions between metabolic dysfunction-associated fatty liver disease and COVID-19

During the outbreak of the coronavirus disease 2019(COVID-19)pandemic,particular interest rose regarding the interaction between metabolic dysfunctionassociated fatty liver disease(MAFLD)and the COVID-19 infection.Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes.One of the proposed mechanisms is the inflammatory response pathway,especially the one involving cytokines,such as interleukin 6,which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver.This should increase our vigilance in terms of early detection,close follow up and early treatment for individuals with MAFLD and COVID-19 infection.In the direction of early diagnosis,biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed.COVID-19 is a newly described entity,expected to be of concern for the years to come,and MAFLD is a condition with an ever-increasing impact.Delineating the interaction between these two entities should be brought into the focus of research.Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective,and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

Coronavirus disease 2019(COVID-19)is an acute respiratory infection caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).SARS-CoV-2 infection typically presents with fever and respiratory symptoms,which can progress to severe respiratory distress syndrome and multiple organ failure.In severe cases,these complications may even lead to death.One of the causes of COVID-19 deaths is the cytokine storm caused by an overactive immune response.Therefore,suppressing the overactive immune response may be an effective strategy for treating COVID-19.Mesenchymal stem cells(MSCs)and their derived exosomes(MSCs-Exo)have potent homing abilities,immunomodulatory functions,regenerative repair,and antifibrotic effects,promising an effective tool in treating COVID-19.In this paper,we review the main mechanisms and potential roles of MSCs and MSCs-Exo in treating COVID-19.We also summarize relevant recent clinical trials,including the source of cells,the dosage and the efficacy,and the clinical value and problems in this field,providing more theoretical references for the clinical use of MSCs and MSCs-Exo in the treatment of COVID-19.

Harnessing immunity:Immunomodulatory therapies in COVID-19

An overly exuberant immune response,characterized by a cytokine storm and uncontrolled inflammation,has been identified as a significant driver of severe coronavirus disease 2019(COVID-19)cases.Consequently,deciphering the intricacies of immune dysregulation in COVID-19 is imperative to identify specific targets for intervention and modulation.With these delicate dynamics in mind,immunomodulatory therapies have emerged as a promising avenue for miti-gating the challenges posed by COVID-19.Precision in manipulating immune pathways presents an opportunity to alter the host response,optimizing antiviral defenses while curbing deleterious inflammation.This review article compre-hensively analyzes immunomodulatory interventions in managing COVID-19.We explore diverse approaches to mitigating the hyperactive immune response and its impact,from corticosteroids and non-steroidal drugs to targeted biologics,including anti-viral drugs,cytokine inhibitors,JAK inhibitors,convalescent plasma,monoclonal antibodies(mAbs)to severe acute respiratory syndrome coronavirus 2,cell-based therapies(i.e.,CAR T,etc.).By summarizing the current evidence,we aim to provide a clear roadmap for clinicians and researchers navigating the complex landscape of immunomodulation in COVID-19 treatment.CS Glucocorticoids are among the most widely prescribed drugs with their immune-suppressive and anti-inflammatory effect[84].The current guidelines for the treatment of COVID-19 recommend against the use of dexamethasone or other systemic CS in non-hospitalized patients in the absence of another indication[70].The RECOVERY trial demonstrates the reduced 28-d mortality among hospitalized patients with COVID-19 using dexamethasone compared to the usual standard of care,along with other investigators,such as Ahmed and Hassan[85].The benefit of dexamethasone was seen only among participants receiving either oxygen alone or invasive mechanical ventilation at randomization but not among those receiving no respiratory support at enrollment[85].In a systematic review and meta-analysis,Albuquerque et al[86]showed that in comparison to tocilizumab,baricitinib,and sarilumab are associated with high probabilities of similar mortality reductions among hospitalized COVID-19 concurrently treated with CS.As a result of the absence of SARS-CoV-2-specific antiviral medications,the effectiveness of COVID-19 treatments is reduced.Several COVID-19 therapies are now under investigation.However,the majority of them lack specificity,efficacy,and safety[87].Immunotherapy is a ground-breaking medical treatment that manipulates the immune system to fight diseases.Translational research is rapidly progressing,recognized as a significant breakthrough in 2013[88].Among the immunotherapeutic options for treating COVID-19 are Immunoglobulin,CP,antibodies,mAbs(mAbs),NK cells,T cells,TLR,cytokine therapies and immune modulators.

COVID-19 and liver injury: An ongoing challenge

The new coronavirus severe acute respiratory syndrome coronavirus 2(SARSCoV-2)was identified in December 2019,in Wuhan,China.The virus was rapidly spread worldwide,causing coronavirus disease 2019(COVID-19)pandemic.Although COVID-19 is presented,usually,with typical respiratory symptoms(i.e.,dyspnea,cough)and fever,extrapulmonary manifestations are also encountered.Liver injury is a common feature in patients with COVID-19 and ranges from mild and temporary elevation of liver enzymes to severe liver injury and,even,acute liver failure.The pathogenesis of liver damage is not clearly defined;multiple mechanisms contribute to liver disorder,including direct cytopathic viral effect,cytokine storm and immune-mediated hepatitis,hypoxic injury,and druginduced liver toxicity.Patients with underlying chronic liver disease(i.e.,cirrhosis,non-alcoholic fatty liver disease,alcohol-related liver disease,hepatocellular carcinoma,etc.)may have greater risk to develop both severe COVID-19 and further liver deterioration,and,as a consequence,certain issues should be considered during disease management.The aim of this review is to present the prevalence,clinical manifestation and pathophysiological mechanisms of liver injury in patients with SARS-CoV-2 infection.Moreover,we overview the association between chronic liver disease and SARS-CoV-2 infection and we briefly discuss the management of liver injury during COVID-19.

Insight into the liver dysfunction in COVID-19 patients: Molecular mechanisms and possible therapeutic strategies

As of June 2022,more than 530 million people worldwide have become ill with coronavirus disease 2019(COVID-19).Although COVID-19 is most commonly associated with respiratory distress(severe acute respiratory syndrome),metaanalysis have indicated that liver dysfunction also occurs in patients with severe symptoms.Current studies revealed distinctive patterning in the receptors on the hepatic cells that helps in viral invasion through the expression of angiotensinconverting enzyme receptors.It has also been reported that in some patients with COVID-19,therapeutic strategies,including repurposed drugs(mitifovir,lopinavir/ritonavir,tocilizumab,etc.)triggered liver injury and cholestatic toxicity.Several proven indicators support cytokine storm-induced hepatic damage.Because there are 1.5 billion patients with chronic liver disease worldwide,it becomes imperative to critically evaluate the molecular mechanisms concerning hepatotropism of COVID-19 and identify new potential therapeutics.This review also designated a comprehensive outlook of comorbidities and the impact of lifestyle and genetics in managing patients with COVID-19.

Implications of metabolic dysfunction associated fatty liver disease in COVID-19

Metabolic associated fatty liver disorder(MAFLD)characterizes the contributing etiologies(i.e.,type 2 diabetes mellitus,metabolic syndrome,overweight)of individuals with fatty liver disease that affects 1/3rd of the world population.In 2020,the coronavirus disease 2019(COVID-19)crisis was unprecedented,and people with different comorbidities became more susceptible to the infection caused by severe acute respiratory syndrome coronavirus 2.MAFLD patients are frequently obese with added metabolic menace like diabetes,hypertension,and dyslipidemia leading to greater jeopardy of COVID-19.MAFLD patients are 4 to 6-fold more prone towards infections.COVID-19 induces liver injury with elevated levels of aspartate aminotransferase and alanine aminotransferase and insignificantly elevated bilirubin.Hence,MAFLD in COVID-19 patients worsens the condition significantly.The evidence highlighting the interaction between MAFLD and altered liver functioning in COVID-19 suggested that COVID-19 patients with pre-existing MAFLD are at greater risk of morbidity or intensive care unit admission.Direct hepatic injury,enhanced levels of inflammatory cytokines,declined hepatic mitochondrial activity,and compromised immunity are considered as some underlying mechanisms.The main focus of this review is to discuss the implications of metabolic dysfunction associated with fatty liver disease in COVID-19 patients.The review systematically analyzes the effect of striking two worldwide pandemics(MAFLD and COVID-19)together in the present era.