The core mechanism of the KD is to reduce carbohydrate intake, thereby lowering blood glucose levels and forcing the liver to switch from glucose metabolism to fatty acid oxidation (34). When carbohydrate intake is reduced, the liver breaks down fatty acids through β-oxidation to produce ketone bodies, such as β-hydroxybutyrate (BHB) and acetoacetate. These ketones not only provide energy for the liver but also serve as energy sources for other tissues, especially the brain (24).

Under normal conditions, the liver primarily generates glucose through glycogenolysis and gluconeogenesis (35). However, during the KD, the reduced glucose availability shifts the liver’s metabolism toward fatty acid oxidation, generating ketones to meet energy demands. This metabolic switch helps reduce the liver’s dependence on glucose, improves glucose metabolism, and promotes fat burning, thus alleviating hepatic fat accumulation—especially in conditions like NAFLD. This dietary shift may offer therapeutic benefits for these pathological states (36).

The KD can significantly improve insulin sensitivity, which is particularly relevant in conditions like insulin resistance, NAFLD, and type 2 diabetes. By substantially reducing carbohydrate intake, the diet stabilizes blood glucose levels and decreases insulin secretion, improving insulin sensitivity (37). As insulin levels decrease, the liver’s expression of key enzymes involved in fat synthesis, such as fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC), is suppressed, reducing fat generation (38).

The KD also plays a crucial role in modulating liver inflammation. Studies have shown that the KD can reduce pro-inflammatory factors in the liver, such as tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), and suppress the activation of pro-inflammatory pathways, like nuclear factor kappa B (NF-κB) (39). By inhibiting inflammation, the KD helps slow down liver damage, particularly in conditions related to fatty liver, such as NAFLD (40).

Furthermore, the KD has beneficial effects on oxidative stress regulation. Ketones, especially β-hydroxybutyrate, not only serve as an energy source but also exhibit antioxidant properties. Ketones activate the nuclear factor erythroid 2-related factor 2 (NRF2) pathway, which enhances the activity of antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx), thus helping to neutralize free radicals and mitigate oxidative stress (41).

In liver diseases such as NAFLD and alcoholic fatty liver, oxidative stress and inflammation are common pathological features (42). The KD, by reducing oxidative stress and suppressing inflammation, has the potential to alleviate these pathological features and slow disease progression.

The KD alters lipid metabolism, which has significant effects on lipid synthesis and breakdown in the liver (43). During ketone body production, fatty acids are broken down via β-oxidation, generating ketones for energy. This metabolic change helps not only reduce fat accumulation in the liver but also promotes the metabolism of lipids and cholesterol.

Studies have shown that the KD may also regulate the synthesis and metabolism of bile acids, further promoting lipid metabolism (44). The liver is the primary site for bile acid synthesis, and the KD can stimulate bile acid production by modulating the fatty acid levels in the liver, helping to reduce fat deposits in the liver.

Although the KD has positive effects on liver health, long-term adherence to the diet may also pose certain risks to the liver. The high-fat nature of the KD may lead to excessive accumulation of cholesterol and fat-soluble vitamins, potentially increasing the liver’s workload, especially in individuals with pre-existing liver conditions (45).

Additionally, the KD may exert pressure on the gallbladder, particularly in individuals with a history of gallstones or compromised gallbladder function. Excessive fat intake may lead to increased gallbladder activity, raising the risk of gallstone formation (46).

Moreover, prolonged ketone production may impose additional stress on the liver, particularly in individuals with impaired liver metabolism. This can lead to deficiencies in fat-soluble vitamins (such as A, D, E, and K), affecting liver function. Therefore, close monitoring of liver function is necessary when following the KD, especially for extended periods, to ensure safety and long-term effectiveness (47).

The KD exerts multiple beneficial effects on liver physiology by modulating lipid metabolism, improving insulin sensitivity, reducing inflammation, and regulating oxidative stress. It shows potential therapeutic benefits for liver diseases, especially in conditions like fatty liver disease, cirrhosis, and certain metabolic disorders. However, the implementation of the KD should be personalized based on the individual’s condition, and long-term use requires close monitoring to minimize potential risks. By designing appropriate KD plans and working with healthcare providers and nutritionists, individuals can maximize the benefits for liver health while minimizing the potential risks associated with its prolonged use.

NAFLD primarily results from the accumulation of excessive lipids in the liver, often linked to insulin resistance and metabolic dysfunction (48). Insulin resistance plays a central role in the pathogenesis of NAFLD by promoting lipolysis and leading to the increased influx of free fatty acids into the liver, where they accumulate and cause hepatic steatosis (49). Additionally, insulin resistance exacerbates itself through a feedback loop, which worsens the metabolic disturbances associated with NAFLD (50).

The KD can positively impact insulin resistance by reducing carbohydrate intake, which decreases glucose availability and stabilizes blood sugar levels (51). This reduction in glucose metabolism lowers insulin demand, helping to maintain lower insulin levels, thereby reducing the incidence of insulin-related metabolic disorders in the liver. Furthermore, during ketosis, the liver converts fatty acids into ketone bodies, which provide an alternative energy source to glucose. This shift significantly reduces the liver’s reliance on glucose metabolism, allowing it to oxidize fatty acids more effectively (28).

Insulin is a key regulator of hepatic lipogenesis, promoting fatty acid synthesis through transcription factors such as sterol regulatory element-binding protein 1c (SREBP-1c) (52). Lower insulin levels, facilitated by the KD, decrease the activity of these transcription factors, which in turn reduces the synthesis of triglycerides from fatty acids and acetyl-CoA, thus mitigating excessive lipid accumulation in the liver (53). Additionally, the KD promotes the breakdown of fatty acids into free fatty acids, further contributing to the reduction of liver fat (37).

BHB, one of the primary ketone bodies, has been shown to activate transcription factors like peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which regulates genes involved in fat metabolism and enhances mitochondrial oxidative capacity (54). By promoting mitochondrial fatty acid oxidation and gene expression related to lipid metabolism, BHB further supports the therapeutic goal of reducing hepatic lipid accumulation (55). However, some studies suggest that the KD may not universally benefit NAFLD, and several factors, including the type and quality of lipids in the diet, the body’s ketogenic reserves, and individual metabolic status, can influence treatment outcomes (56). Research is ongoing to elucidate the full range of effects the KD has on liver lipid metabolism and its potential for managing NAFLD.

It should be noted that in recent years, the term “NAFLD” has gradually been replaced by “metabolic-associated fatty liver disease” (MASLD) (57). The introduction of the term MASLD is a significant advancement in the understanding of this condition, reflecting a more precise classification based on its metabolic associations. While “Non-Alcoholic Fatty Liver Disease” (NAFLD) historically emphasized the exclusion of alcohol consumption, MASLD highlights the disease’s close links with metabolic disorders such as obesity and diabetes. This shift in terminology is necessary as it aligns with the evolving understanding of the disease’s pathophysiology and its connection to metabolic syndrome, offering a more accurate representation of its etiological factors. Furthermore, adopting MASLD in epidemiological research enhances the precision of patient categorization, contributing to better disease stratification and more tailored clinical management. Although the transition from NAFLD to MASLD may pose challenges, particularly regarding historical data, it is a crucial step toward advancing both research and clinical practice.

Chronic alcohol consumption leads to persistent inflammation, hepatocyte damage, and fibrosis, often progressing to alcoholic fatty liver disease (ALD) and eventually cirrhosis (58). While complete alcohol abstinence remains the primary treatment for ALD and cirrhosis, addressing the metabolic dysfunction in the liver is also crucial. The goal is to reduce hepatic fat accumulation, control inflammation, and mitigate oxidative stress, all of which contribute to liver injury (14).

The KD, with its low carbohydrate content, reduces external glucose availability, encouraging the liver to shift its primary energy source from glucose to fatty acids. This metabolic switch boosts fat oxidation and promotes the breakdown of lipids (59). During ketosis, the liver upregulates metabolic regulators like fibroblast growth factor 21 (FGF21), which facilitates ketone production, particularly BHB (60). BHB plays a significant role in managing alcoholic fatty liver and early cirrhosis by improving insulin sensitivity, reducing hepatic fat accumulation, and providing antioxidant protection against oxidative stress (61). BHB has several mechanisms through which it exerts its beneficial effects. It interacts with G-protein-coupled receptor 109A (GPR109A), triggering anti-inflammatory signaling pathways and suppressing pro-inflammatory pathways mediated by NF-κB (62). This results in reduced cytokine production, such as TNF-α, IL-1β, and IL-6, which are key mediators of inflammation. Additionally, BHB enhances the production of anti-inflammatory cytokines like IL-10 and supports the shift of macrophage polarization toward the M2 phenotype, contributing to reduced inflammation and enhanced tissue repair (63). Oxidative stress, a common feature in ALD, is exacerbated by alcohol metabolism, which generates excessive reactive oxygen species (ROS) (64). BHB stabilizes cell membranes and scavenges free radicals, reducing oxidative damage. Moreover, it stimulates the NRF2 pathway, which upregulates antioxidant enzymes like superoxide dismutase (SOD) and glutathione peroxidase (GPx) (65). These enzymes neutralize ROS, reducing further cellular damage. The antioxidant-rich foods typically included in a KD, such as nuts, seeds, and leafy greens, further support the body’s antioxidant defenses, enhancing the diet’s overall effectiveness in mitigating liver damage (66).

In summary, the KD addresses the metabolic disturbances associated with ALD and early cirrhosis by shifting liver metabolism toward enhanced fatty acid oxidation and ketone production. Through the actions of BHB, the diet improves insulin sensitivity, reduces hepatic fat deposition, and exerts anti-inflammatory and antioxidant effects, making it a promising adjunct therapy for managing alcoholic fatty liver disease and early cirrhosis.

HCC is a primary form of liver cancer that often develops in the context of chronic liver diseases, including cirrhosis and hepatitis (67). The KD has shown promise in influencing the progression of HCC by altering tumor cell metabolism. Many cancer cells, including those in HCC, rely heavily on glycolysis for energy, even in the presence of oxygen (the Warburg effect). The KD reduces glucose availability, potentially limiting tumor cell growth by depriving them of their preferred energy source (68).

In contrast to normal cells, which can effectively utilize ketone bodies as an alternative energy source, HCC cells struggle to adapt to ketosis due to mitochondrial dysfunction and abnormal ketone metabolism (69). Key enzymes involved in ketone metabolism, such as Alpha-ketoglutarate dehydrogenase and succinyl-CoA transferase, are often less active in tumor cells, preventing efficient utilization of ketones. This metabolic disruption inhibits tumor growth and proliferation, offering a potential therapeutic benefit (70).

Additionally, the increased production of ketone bodies like β-hydroxybutyrate under a KD has been shown to enhance oxidative stress in tumor cells (71). While ketones reduce ROS production in normal cells, tumor cells, with their impaired mitochondria, experience heightened oxidative stress under a KD (72). This stress may promote apoptosis and autophagy in tumor cells, contributing to tumor reduction. The KD can also inhibit angiogenesis, the process by which tumors develop blood vessels to supply nutrients, further limiting tumor growth (73).

The KD’s ability to alter the metabolic environment of HCC cells, enhance oxidative stress, and potentially sensitize tumors to chemotherapy or radiotherapy makes it a promising adjunct treatment (69). Studies have shown that combining a KD with other therapeutic strategies, such as small molecule inhibitors or statins, may synergistically enhance treatment outcomes. These treatments work by inhibiting cancer cell growth and metabolism while promoting tumor cell apoptosis (74).

In summary, the KD’s impact on tumor cell metabolism, its ability to increase oxidative stress in cancer cells, and its potential to improve the effectiveness of conventional therapies make it a promising adjunctive treatment for HCC.

One of the key therapeutic benefits of the KD is its ability to reduce liver fat accumulation, especially in cases of NAFLD. By limiting carbohydrate intake and shifting the body’s energy reliance from glucose to fats, the KD encourages fat oxidation and ketone production. However, improper fat selection and excessive fat intake can exacerbate fat accumulation in the liver, especially if the liver has not yet fully adapted to the ketogenic state. This can lead to an aggravation of hepatic steatosis (fatty liver), particularly in individuals with pre-existing liver damage (75).

Studies suggest that in some cases, the KD may induce metabolic dysregulation in liver fatty acid metabolism, causing an accumulation of triglycerides and free fatty acids within hepatocytes (76). This issue may be particularly dangerous for individuals who already have compromised liver function, as the excess lipid deposition can further impair liver function and accelerate liver injury. Additionally, the composition of fats in the diet is crucial; if the diet includes high levels of unhealthy fats, it may not only contribute to increased liver fat but could also potentially elevate the risk of liver fibrosis and other complications over time (77).

The KD imposes a significant metabolic burden on the liver, particularly in individuals whose liver function is already compromised (78). During ketosis, the liver plays a central role in metabolizing fatty acids and converting them into ketone bodies for energy. This metabolic shift requires the liver to accelerate the oxidation of fatty acids, which can increase the liver’s workload.

For individuals with pre-existing liver disease or reduced hepatic function, this increased metabolic stress may lead to further liver damage. Chronic, excessive oxidative stress and the increased demand for fatty acid metabolism can strain hepatocytes, potentially leading to liver dysfunction or even liver failure in extreme cases (79). Moreover, the accumulation of ketone bodies, while beneficial in many instances, could overwhelm liver detoxification mechanisms in individuals with liver disease, complicating the clinical picture and potentially exacerbating hepatic injury (80).

Another potential side effect of the KD is an increase in cholesterol levels, which could contribute to the formation of gallstones (81). The high-fat nature of the diet leads to increased cholesterol synthesis in the liver and increased secretion of cholesterol into the bile. Although bile acids play a crucial role in the digestion and absorption of fats, excessive cholesterol levels can overwhelm the liver’s ability to process and excrete it via bile (82).

For individuals with pre-existing high cholesterol or those who have a history of gallstones, the KD could pose an additional risk by promoting the formation of new gallstones (83). The high intake of dietary fats, particularly saturated fats, may increase the risk of bile becoming supersaturated with cholesterol, which is a known precursor to gallstone formation. Therefore, individuals with a history of gallstones or those at risk should be cautious when considering the KD, as it may exacerbate their condition.

The strict nature of the KD, which severely restricts carbohydrate intake and emphasizes fats and proteins, could lead to certain nutrient deficiencies over time. While the diet can be rich in vitamins A, D, E, and K due to its high-fat content, it may lack essential nutrients found in carbohydrate-rich foods, such as certain B vitamins, fiber, and antioxidants (84). The lack of these nutrients can potentially lead to gastrointestinal issues, muscle cramps, or even bone health problems due to insufficient vitamin D and calcium (85).

Additionally, certain liver diseases, such as cirrhosis, can already compromise the liver’s ability to process and store essential nutrients. In these cases, the KD may exacerbate nutrient imbalances, further impairing liver function and overall health. Therefore, careful monitoring of nutrient levels and supplementation may be required for individuals with liver disease following a KD (86).

While the KD has anti-inflammatory properties for many individuals, it may have the opposite effect in others, especially those with compromised liver function. In individuals with existing liver inflammation, such as those with ALD or autoimmune hepatitis, the KD may initially exacerbate liver inflammation, especially during the early phases of adaptation. This could lead to an increase in liver enzymes, liver swelling, or discomfort (87).

Furthermore, if the KD is not well-balanced in terms of fat types or if the intake of inflammatory fats is high, it could lead to an inflammatory response within the liver, potentially aggravating liver conditions and impairing liver function. Careful attention to the quality of fats in the diet is essential to mitigate this risk, especially in individuals with underlying liver pathology (88).

While the KD offers significant therapeutic potential for liver diseases such as NAFLD and ALD, it is essential to consider the potential side effects on liver health. These include the increased risk of liver fat accumulation, elevated metabolic burden on the liver, higher cholesterol levels, nutrient deficiencies, and exacerbated liver inflammation. As such, the KD should be approached with caution, particularly in individuals with pre-existing liver dysfunction or other metabolic conditions. It is highly recommended that individuals considering or currently following the KD do so under the supervision of a healthcare professional to ensure safe and effective implementation and to monitor for any potential adverse effects.