The development of MAFLD is closely related to lifestyle factors, especially excess caloric intake paired with insufficient physical exercise (40). Current studies suggest that dietary intervention improves MAFLD with or without physical activity, and training also reduces hepatic steatosis with or without dietary intervention (41). The 2018 ASSLD Practice Guidelines state that a combination of a low-calorie diet and moderate-intensity exercise may lead to sustained weight loss over time, with a 3–5% weight loss improving steatosis and a 7–10% weight loss improving fibrosis (42). However, relevant clinical trials found that most patients could not achieve the level of weight loss that can improve liver fibrosis (43). It is difficult to achieve the goal of enhancing fibrosis through lifestyle intervention alone. A recent prospective cohort study found that healthy lifestyles positively correlate with all-cause mortality in MAFLD patients (44). The COVID-19 pandemic has affected people's lifestyles seriously, and new MAFLD diagnoses have increased during the pandemic. A retrospective study including 973 participants found that before the pandemic (2018–2019), the independent lifestyle predictor of MAFLD was regular late-night eating, while in the epidemic (2019–2020), it was higher daily alcohol intake (45). The research in mice showed that respiratory exposure to silica nanoparticles induces hepatotoxicity, resulting in inflammatory infiltration, and even causes the deposition of collagen (46). Another cross-sectional study conducted in China proves that the rising sickness rate of MAFLD in the real world is significantly related to long-term exposure to ambient PM1, PM2.5, PM10, and NO2, particularly those who are men, alcohol drinkers, cigarettes smokers, high-fat diet consumers, and central obesity (47). Lifestyle changes make MAFLD more and more common. There is no doubt that healthy lifestyles can help prevent the occurrence of MAFLD, and timely change in unhealthy lifestyles is very important for MAFLD patients. However, as a preventive strategy that can be extended to the whole population, lifestyle interventions alone have yet to control the prevalence of MAFLD and the development of MAFD-related liver fibrosis, so we must actively explore other preventive and therapeutic measures.

Bariatric metabolic surgery is now recommended as an effectual treatment for clinically severe obesity and its interrelated comorbidities and has generally been accepted by patients in recent years (48). In a bariatric metabolic surgery center in France, Guillaume Lassailly conducted a long-term follow-up on 180 severely obese patients who were biopsy-confirmed with NASH and underwent bariatric metabolic surgery; they found that 84% of the participants had regression of NASH in liver samples after 5 years, indicating that the fibrosis of the liver was reduced from the first to the fifth year (32). Although it is generally believed that MAFLD is closely related to obesity, there is growing evidence proving that not all overweight individuals have MAFLD. Approximately 40% of MAFLD patients are classified as non-obese (49, 50). Does bariatric metabolic surgery have a therapeutic effect on low BMI MAFLD patients? Adrian T Billeter researched the curative effect of Roux-en-Y gastric bypass (RYGB) in advanced MAFLD; 20 patients participated in this prospective trial and underwent RYGB surgery; liver biopsy was performed during the operation and followed up 3 years later. The results showed that after 3 years of RYGB treatment, MAFLD completely disappeared in all patients, and fibrosis was also improved, 55% of the patients stopped insulin therapy, glycosylated hemoglobin decreased significantly, new lipogenesis decreased, β-oxidation was enhanced, and finally, the secretion of gastrointestinal hormones and adipokines was favorably altered (51). The aforementioned results suggest that bariatric metabolic surgery positively affects MAFLD regardless of obesity, but there are still certain risks in these surgical treatments for MAFLD. For example, the mortality rate of patients with decompensated liver cirrhosis after bariatric metabolic surgery is as high as 16.3% (52). Therefore, bariatric metabolic surgery is excluded as the first-line treatment of MAFLD. It is believed that with the continuous improvement of relevant clinical research, clinicians can more accurately evaluate the pros and cons of bariatric metabolic surgery for MAFLD, better grasp the indications for surgical treatment, and make more patients benefit from it.

Because of the severe scarcity of liver resources, the high cost of liver transplantation (LT), and a series of problems, such as immune rejection after transplantation, LT is just considered for advanced MAFLD patients with severe complications in most cases. However, it cannot be ignored that MAFLD is the fastest-rising indication for LT in Western countries. Its interrelated end-stage liver disease and HCC have grown to be LT's common indications worldwide (2). Severe cirrhosis, liver failure, and severe portal hypertension caused by advanced liver fibrosis usually require LT. Some patients with non-resettable HCC also need LT for better treatment (53, 54). Although the survival rate of liver transplant recipients with MAFLD is similar to that of liver transplant recipients with other etiologies, liver transplant recipients still seem prone to relapse MAFLD due to the persistence of diseases such as metabolic syndrome (55). This proportion is as high as 78–88%, usually relapsing within the first 5 years after LT. However, ~11–14% may develop cirrhosis within 5 years after LT (56). As the number of liver transplant recipients continues to increase, their quality of life continues to improve, their survival time continues to increase, and increased attention has been paid to the occurrence of MAFLD after transplantation. In addition, due to the shortage of liver resources and the prevalence of MAFLD, some donor livers with steatosis also need to be used in LT.

Pharmacological treatment is very attractive to MAFLD and liver fibrosis, not only due to its convenience but also because various mechanisms of disease progression can be targeted. At present, many drugs are actively developed for the therapy of MAFLD and its related liver fibrosis, which are mainly divided into the following categories according to the main mechanism (18, 57): The first category is agents acting on lipid syntheses and fat accumulation, such as glucagon-like peptide 1 (GLP-1) agonists, ACC inhibitors, Fanitol X receptor (FXR) agonists, and PPAR-α/δ agonists. The second category is drugs that act on cellular stress and apoptosis, including vitamin E and caspase inhibitors. The third category is drugs that play roles in the immune and inflammatory response, such as C-C chemokine receptor type 2 and type 5 antagonists. The fourth category is drugs that directly target the fiber formation process, such as LOXL2 monoclonal antibodies. In addition, new studies have also found that anti-angiogenic drugs can improve liver fibrosis, such as recombinant vascular endothelial growth factor (rVEGF) and bevacizumab (58). These drugs have some efficacy in the therapy of MAFLD and its associated liver fibrosis. However, few pharmacological treatments reached satisfactory endpoints assessed by liver biopsy or with negligible side effects in clinical trials (18). It is essential to accelerate the discovery of new pharmacotherapeutics and explore better multi-drug combination therapies.

In summary (Table 1), measures such as lifestyle intervention have failed to effectively control the increasing prevalence of MAFLD and the progression of liver fibrosis. Bariatric metabolic surgery is still not suitable as the first-line treatment for MAFLD. LT, an option method to save lives for patients with MAFLD-related non-resettable HCC or end-stage liver diseases, is not a good solution for decreasing the burden of MAFLD and its associated liver fibrosis. In addition, the advance of MAFLD-related liver fibrosis involves numerous complicating factors, and the impact of single-drug therapy is very limited. Effective pharmaceutical therapies may need to consider multiple mechanisms, such as metabolic disorders, inflammation, immunity, and fibrosis. Combination pharmaceutical therapies may be an inevitable choice to achieve adequate control of MAFLD and its related liver fibrosis in the future.

Glucagon-like peptide 1 (GLP-1), a pleiotropic peptide hormone secreted by intestinal L cells (59), controls insulin hormone secretion, intestinal motility, and body weight. GLP-1 receptor agonists, developed for treating T2DM and obesity recently, have demonstrated a favorable benefit and decreased the occurrence of cardiovascular-related adverse events in T2DM patients. The current analysis considers all people with T2DM, and people with a liver fat content of >5% are deemed to have MAFLD (60). MAFLD increases cardiovascular morbidity and mortality (18). In recent years, the potential role of the combination therapy of GLP-1 receptor agonists and sodium–glucose cotransporter-2 (SGLT-2) inhibitors in treating MAFLD has attracted increased attention. Numerous clinical trials link this combination treatment to reductions in intrahepatic triglyceride accumulation and liver fibrosis, even though none of the GLP-1 or SGLT-2 receptors are expressed in the liver (61). Therefore, GLP-1 receptor agonists are a potentially valuable element of combination therapy to address different complementary pathways in MAFLD therapy (62). For example, in a 24-week exploratory phase 2 trial, the GLP-1 receptor agonist semaglutide alleviates cilofexor and firsocostat-induced hypertriglyceridemia, resulting in more significant reductions in liver enzymes, liver fat, and non-invasive imaging assessed liver fibrosis (NCT03987074) (63). In conclusion, GLP-1 receptor agonists are very suitable as the primary drugs for the combination therapy of MAFLD characterized by metabolic disorders.

Acetyl-CoA carboxylase (ACC) is a critical enzyme in de novo lipogenesis (DNL), catalyzing the rate-limiting step in converting acetyl-CoA to malonyl-CoA, regulating the fatty acids' mitochondrial β-oxidation and playing a vital role in the accumulation of TG in hepatocytes. Animal studies have confirmed that inhibiting ACC in rat models can reduce liver fibrosis (18). Currently used ACC inhibitors mainly include firsocostat (formerly GS-0976) and PF-05221304. These two acetyl-CoA carboxylase inhibitors affect serum TG. In a study of NASH patients, it was found that treating with GS-0976 20 mg per day for 12 weeks reduced liver steatosis, selective markers of liver fibrosis, and biochemistry but caused significant increases in serum TG levels in most patients (64); this asymptomatic hypertriglyceridemia can be partially resolved by fibrate (belonging to PPARα agonists). Lawitz EJ compared the curative effects of Vascepa or fenofibrate in mitigating triglyceride elevation in patients with NASH treated with cilofexor and firsocostat. NASH patients with elevated TG were randomly divided into two groups: one group treated with Vascepa 2 g twice a day for 2 weeks, and another with fenofibrate 145 mg once a day; both groups followed these with cilofexor 30 mg and firsocostat 20 mg once a day for 6 weeks, then safety, blood lipids, and liver biochemistry were monitored. After 6 weeks of combination therapy, fenofibrate has a better curative effect than Vascepa in reducing elevated TG in patients (NCT02781584) (65). Similarly, the ACC inhibitor PF-05221304 alone significantly reduced hepatic steatosis and induced an asymptomatic increase in serum TG levels; the latter may represent an adverse cardiometabolic profile limiting the long-term use of this class of drugs (66). Diacylglycerol acyltransferase 2 (DGAT2) is an enzyme that catalyzes the last step of TG synthesis. It plays a role in regulating VLDL production in rodents (67); PF-06865571 is an inhibitor of DGAT2 (68). In a Phase 2a pilot study combining PF-05221304 and PF-06865571, a significant attenuation of ACC inhibitor-mediated effects on serum TG was observed (NCT03776175) (69). We look forward to longer-period research including liver biopsies to further demonstrate the impact of co-administration of PF-05221304 and PF-06865571 on NASH regression and fibrosis in NASH patients. In summary, ACC inhibitors are currently attractive target drugs to restore the balance of hepatic fatty acid metabolism in patients with MAFLD. Combined use with drugs, such as FXR agonists, can reduce liver fibrosis, but attention still needs to be paid to the combination use of other medications that regulate lipogenesis to minimize the impact on blood lipids.

Fanitol X receptor (FXR) is a nuclear receptor abundantly expressed in the liver and intestinal epithelia, which is vital in the perception of bile acid signals. It regulates inflammatory pathways by reducing pro-inflammatory cytokines, inhibiting the activation of inflammasomes, and upregulating anti-inflammatory mediators (70). Studies have confirmed that activating the FXR in HSCs can reduce the HSCs' response to profibrotic signals such as TGFβ, thereby decreasing ECM formation and inhibiting the development of fibrosis (71). FXR agonists mainly include obeticholic acid (OCA) and cilofexor. One serious limitation of the OCA therapy is dyslipidemia (elevated low-density lipoprotein cholesterol), which may lead to a rising risk in NASH patients with atherosclerosis. The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) plays a pivotal role in the biosynthesis of cholesterol; HMGR inhibitors inhibit cholesterol synthesis by atorvastatin (72). Clinical research about the combination of OCA and a statin found that atorvastatin attenuated OCA-induced low-density lipoprotein cholesterol (LDL-C) elevation in patients with NASH after 16 weeks of treatment (NCT02633956) (73). Cilofexor can significantly reduce liver steatosis, biochemical markers, and serum bile acid levels. Studies have shown that it has better anti-fibrosis profit when combined with ACC inhibitor firsocostat but still faces the problem of hypertriglyceridemia (NCT03449446) (53). This issue limits the application of this pharmacological combination therapy strategy. Therefore, it is necessary to explore more precise and effective drug targets; otherwise, multi-drug combination therapies are needed. As previously mentioned, adding fenofibrate or semaglutide relieves elevated TG induced by the combination therapy of cilofexor and firsocostat (63, 65). In addition, the FXR receptor agonist tropifexor and the C-C chemokine receptor type 2 and type 5 antagonist cenicriviroc target steatosis, inflammation, and fibrosis pathways involved in MAFLD. FXR agonists, which restore bile acid metabolism and suppress inflammation, are essential to future combination therapy for MAFLD.

Peroxisome proliferator-activated receptors (PPARs) are a class of nuclear hormone superfamily receptors widely involved in regulating inflammatory responses and metabolic homeostasis. Some agonists targeting PPAR combined with other different classes of drugs have a complementary effect in treating liver fibrosis, such as fenofibrate mentioned above (65, 74). In addition, pemafibrate is a selective PPARα modulator, and clinically relevant doses of pemafibrate were demonstrated to effectively and safely lower serum TG in mice (75). A study containing 118 patients evaluated the therapeutical effect of pemafibrate for MAFLD patients and showed that pemafibrate reduced liver stiffness but had no effect in reducing liver fat content (76). Pemafibrate may be a hopeful drug for treating MAFLD combined with medicines to lower hepatic fat. Another trial, including 70 participants with ultrasound-confirmed MAFLD, showed that the combination of ezetimibe plus rosuvastatin lowered hepatic fat (77). Further studies are needed to determine whether the combined use of pemafibrate, ezetimibe, and rosuvastatin can achieve more clinical benefits. In addition, a mouse model study showed that, at the two-time points of onset of NASH progression and HCC survival, combined treatment with pemafibrate and tofogliflozin (an SGLT-2 inhibitor) not only significantly relieved hyperglycemia and hypertriglyceridemia but also reduced ballooning of hepatocytes, reduced expression of ER stress-related genes level (such as Ire1a, Grp78, Xbp1, and Phlda3), and significantly improved the survival rate and decreased the tumors' numbers in the liver. It suggests that PPARα modulator and SGLT-2 inhibitor combined treatment has the potential to inhibit the progression of NASH to HCC (78). Pioglitazone belongs to the first-generation thiazolidinediones, which is a PPARγ agonist, and it was proved that pioglitazone could improve liver fibrosis scores in non-diabetic patients with NASH (79). In patients with T2DM and MAFLD, 32 suitable patients were treated with pioglitazone and tofogliflozin; compared with every single-drug therapy group, combination therapy gained additional improvement in HbA1C. Weight gain mediated by pioglitazone was reduced with the concomitant use of tofogliflozin (80). In conclusion, agonists of PPAR are widely involved in regulating metabolic homeostasis and inflammatory response, have therapeutic potential in preventing the progression of MAFLD to HCC, and have a prominent position in combination therapy.

Up to now, there is no specific clinically useful therapy for MAFLD, thus some people try to screen and study natural products or synthetic compounds to find efficacious drugs for the treatment of MAFLD, such as the natural sesquiterpene ketone (Nok) (81), hydroxytyrosol (HXT), and vitamin E. Both HXT and vitamin E have good antioxidant properties (82), and oxidative stress is an influential factor that induces HSCs to activate and leads to liver fibrosis (83). HSCs can be activated by tumor growth factor TGF-β, leading to a significant increase in proliferation rate (84). Nadia Panera used this cell as an in vitro model to conduct experiments, indicating that the use of HXT and vitamin E alone or in combination treatment resulted in a marked decrease in this TGF-β-dependent pro-proliferative effect. The combined therapy of HXT + vitamin E more effectively inhibited the impact of TGF-β on HSCs. HXT + vitamin E significantly reduced the pattern of liver fibrosis observed in a mouse model which was fed a carbon tetrachloride plus Western diet (82). In addition, in children with biopsy-proven MAFLD, a 4-month-old short-term HXT + vitamin E treatment responds to DNA damage recovery by increasing circulating IL-10 levels, ultimately ameliorating steatosis and hypertriglyceridemia, reducing the fibrosis stage in children with MAFLD, and this beneficial effect is extended over time (NCT02842567) (85). Screening and research on natural products or synthetic compounds to treat MAFLD will help explore new antifibrotic therapeutic targets, which may provide new elements for pharmaceutical combination therapies.

Liver fibrosis is due to the excessive formation of extracellular matrix, often accompanied by neovascularization and changes in vascular structure, ultimately causing organ injury and failure (86, 87). In recent years, angiogenesis inhibitors such as bevacizumab have made great progress in the treatment of tumors (88). Simultaneously, people are also actively exploring the application of angiogenesis modulators in treating liver fibrosis. The microvessels in the liver contain portal veins, hepatic sinusoids, and central vessels, and different vessels play different roles in the development of liver fibrosis (58). Therefore, achieving effective anti-fibrosis through targeted vascular therapy may require a combination of varying angiogenesis modulators. Leukocyte cell-derived chemotaxin 2 (LECT2), a newly discovered hepatic factor, is significantly increased in MAFLD patients (89). Ec-specific receptor Tie1 is necessary for the maturation of blood vessels. Meng Xu found that direct binding of LECT2 to Tie1 can inhibit portal vein angiogenesis, induce hepatic sinusoidal capillarization, and promote liver fibrosis. On the other hand, adeno-associated virus vector serotype 9 carrying LECT2 short hairpin RNA (AAV9-LECT2-shRNA) can target mouse LECT2 to inhibit LECT2/Tie1 signaling, thereby inducing portal angiogenesis, suppressing hepatic sinusoidal capillarization, and alleviating liver fibrosis (90). Yuan Lin and Meng Xu further explored the effect of AAV9-LECT2-shRNA combined with rVEGF or bevacizumab in the targeted therapy of liver fibrosis in mice. The shortcomings of bevacizumab and rVEGF in regulating different microvessels in the treatment of liver fibrosis are made up for by AAV9-LECT2 shRNA, the combination of varying angiogenesis modulators further improves the therapeutic effect on liver fibrosis, and the side effects of bevacizumab combination therapy are relatively less (58). In comparison, vascular endothelial cell regulators are aimed at the changes of angiogenesis in the development of liver fibrosis, directly anti-fibrosis, and in combination with other drugs targeting metabolic disorders, inflammation, and other mechanisms; theoretically speaking, the complementary advantages are apparent, and it is a direction worth exploring.