Liver cancer (LC) ranks among the most common and lethal malignant tumors globally, with its disease burden steadily rising over recent decades^[1]. Hepatitis B and C viruses constitute the leading etiological factors, while excessive alcohol consumption has emerged as an increasingly prominent driver, driven by prevalent alcohol abuse worldwide^[2].

Alcohol triggers hepatocellular injury, persistent hepatic inflammation, fibrosis and cirrhosis, ultimately promoting malignant transformation^[3]. Distinct from viral hepatitis, alcoholic liver disease progression is closely modulated by drinking habits and genetic susceptibility^[4]. Its clinical spectrum covers asymptomatic early lesions to decompensated cirrhosis complicated with portal hypertension. Alcoholic liver disease generally advances more rapidly and is frequently diagnosed at advanced stages^[5].

Unlike LC caused by viral hepatitis^[6] and non-alcoholic fatty liver disease^[7], LC due to alcohol use (LCA) features an occult onset, accompanied by limited therapeutic options and difficult early detection^[8,9] compared with liver cancer induced by viral hepatitis and non-alcoholic fatty liver disease. Relevant prevention and management strategies remain underdeveloped. Given substantial interregional and international disparities in liver cancer burden, targeted intervention formulation faces great challenges^[10]. Existing studies lack comprehensive assessments on LCA mortality patterns and geographic heterogeneity, particularly long-term projections. This study therefore analyzed three-decade LCA mortality trends and regional discrepancies, and predicted disease dynamics until 2050, aiming to furnish evidence for global public health policy design and preventive strategy optimization.

This study comprehensively analyzed the global, regional and national mortality burden of LCA from 1990 to 2021 and further predicted its epidemiological trends through 2050. Globally, LCA ASMR exhibited an upward trend during 1990-2021, with the most rapid increase observed in the Americas and the highest mortality level recorded in Europe in 2021. The high SDI quintile and high-income areas consistently bore the greatest number of deaths. Population growth and age structure were the main contributors to rising global LCA deaths, and population aging is projected to remain a dominant contributing factor through 2050. Substantial global heterogeneity in LCA mortality was identified across different populations, income strata, healthcare capacities, and socioeconomic conditions. These findings demonstrate the evolving epidemiological profile of LCA within the overall liver cancer mortality burden and underline the necessity of targeted and tailored public health intervention strategies.

The pronounced temporal and spatial disparities in LCA ASMR identified in this study highlight the urgent demand for standardized and systematic frameworks for LCA prevention, early diagnosis, population assessment, and clinical treatment. Overall, the global LCA mortality burden gradually increased during 1990-2021 but is projected to plateau and slowly decline in the future. The Americas showed the most rapid growth in ASMR, and Europe held the highest ASMR in 2021, which were consistent with the distribution of alcohol consumption^[12]. In contrast, the Eastern Mediterranean region presented the lowest LCA ASMR, which corresponded to local reductions in alcohol intake. Regional alcohol consumption patterns have diverged substantially: per-adult alcohol consumption has risen sharply across Asia and Africa, while declining in North America, South America, and Europe^[13]. Although improved public health awareness and reduced alcohol exposure have contributed to LCA mortality declines in several regions, low-income settings and populations with insufficient access to healthcare continue to endure a disproportionately heavy LCA mortality burden. Notably, African females sustained the highest LCA ASMR over the study period. This observation is consistent with prior evidence documenting prominent socioeconomic inequities in the prevalence and prognostic outcomes of alcohol-related liver disease^[14]. Further in-depth research focusing on epigenetic mechanisms, individual disease susceptibility, and gender-specific biological and social determinants is warranted to elucidate the distinct gender disparities in LCA epidemiology.

The geographical distribution of the highest LCA ASMR has gradually transitioned from low-income to high-income regions over the past three decades, whereas high-income settings have persistently exhibited the greatest absolute number of LCA-related deaths. A similar epidemiological shift was also observed across SDI stratifications. Population aging represents a critical risk factor for liver cancer, and the more severe aging burden in high-income regions substantially elevates LCA mortality risk^[15]. In addition, alcohol consumption constitutes another predominant modifiable driver of LCA epidemiology, with higher per capita alcohol intake commonly documented in high-income populations. Alcohol use disorder (AUD) can cause a series of physical damages. However, the main cause of alcohol-related deaths is alcohol-associated liver disease (ALD). In some countries, the mortality rate due to alcohol-related causes caused by ALD is almost 90%^[13]. Furthermore, the contribution of alcohol to the LC burden continues to rise, especially in high-income countries^[16]. These synergistic drivers underscore a transitioning epidemiologic landscape for LCA. Continued trends may escalate ASMRs in high-income areas without coordinated prevention strategies.

Viral hepatitis (HBV and HCV) has historically been the predominant etiology of hepatocellular carcinoma (HCC). With widespread HBV vaccination and the availability of potent direct-acting antivirals (DAAs) for HCV, the viral contribution to liver cancer is gradually declining, leading to a more complex, multifactorial epidemiological landscape. Accumulating evidence indicates that alcohol consumption and metabolic dysfunction-associated steatotic liver disease (MASLD) have become the fastest-growing risk factors for liver cancer worldwide^[2]. These etiological factors often exert synergistic rather than independent effects, such that alcohol exposure further elevates liver cancer risk in individuals with pre-existing metabolic or viral liver diseases. Recent clinical data have further demonstrated the evolving epidemiology and prognostic profiles of LCA^[17,18]. Registry-based evidence from Florida has documented a continuous rise in LCA incidence, with an annual percentage increase of 6.0% between 2010 and 2018, disproportionately affecting ethnic minorities, particularly Puerto Rican and Mexican subgroups^[19]. Alcohol-attributable mortality has also risen sharply, with a notable surge during the COVID-19 pandemic^[20,21]. Correspondingly, LCA has become a leading indication for liver transplantation, accounting for 41% of all liver transplantations in 2022^[22,23]. In patients with mild-to-moderate AUD without critical complications, substantial alcohol reduction can yield clinical benefits, whereas strict abstinence markedly improves survival in patients with alcohol-related cirrhosis^[5]. Integrated therapeutic strategies combining liver disease management and addiction treatment have also achieved favorable outcomes in patients with advanced ALD^[24].

Despite ongoing advances in the understanding and management of LCA, substantial regional disparities in disease burden persist. Low-income countries and populations with restricted healthcare access continue to bear a disproportionate LCA mortality burden, particularly African females, who consistently exhibit the highest LCA ASMR. Therefore, intervention measures must combine clinical progress with socio-economic factors. In regions with lower income levels, healthcare access remains a critical factor shaping LCA burden. In the United States, ethnic disparities and income inequality and lower socioeconomic status are correlated with increased LC mortality, particularly in areas with high unemployment or housing issues^[25]. In China, geographical disparities in liver cancer mortality are driven by poverty, limited healthcare access, and environmental pollution; industrial areas suffer higher mortality due to excessive alcohol consumption and substandard healthcare infrastructure^[26]. Notably, significant LCA mortality differences also exist between geographically and demographically similar neighboring countries. In East Asia, for example, Mongolia and South Korea have disproportionately high LCA ASMR. In 2022, South Korea recorded a per capita alcohol consumption of 8.4 liters, exceeding 6.3 liters in Japan and 4.8 liters in North Korea^[27]. South Korea also has a markedly higher prevalence of heavy drinking, driven by high spirits (particularly soju) consumption, which is closely associated with socioeconomic stress and prevalent workplace drinking norms^[28,29]. Cross-national disparities in LCA burden are collectively attributed to variations in healthcare system capacity, obesity and metabolic syndrome prevalence, alcohol consumption patterns, and public health policies. Mitigating global LCA-related health inequities requires addressing fundamental income inequality, expanding healthcare access for vulnerable populations, and reforming high-risk drinking cultures and social norms.

Frontier analysis revealed substantial cross-national disparities in the efficiency of LCA mortality control. While countries such as Brazil have attained near-optimal ASMR reductions via effective public health interventions, many low- and middle-income regions continue to face a heavy LCA mortality burden^[30]. LCA mortality is largely preventable through population-level policy restrictions on alcohol accessibility. Although lifelong alcohol abstinence is critical for improving long-term clinical outcomes, sustained abstinence remains challenging for ALD patients with comorbid AUD. This underscores the necessity of a full-cycle, multidisciplinary management model involving hepatologists, addiction specialists, and social workers to optimize patient care^[5].

Our findings provide a roadmap for region-specific public health interventions. Given the rapidly rising in LCA burden in the Americas, local governments should prioritize WHO-recommended “Best Buys” interventions, including higher alcohol excise taxes and stricter regulation of alcohol marketing. Furthermore, considering that population aging will remain the dominant driver of LCA mortality through 2050, public health strategies should shift from universal health education to precise targeted surveillance. Regular liver ultrasound and alpha-fetoprotein (AFP) screening are strongly recommended for elderly populations with a long-term drinking history as part of routine physical examinations. For African regions with persistent high LCA burden despite declining mortality trends, policy efforts should focus on strengthening primary healthcare infrastructure to facilitate community-based early diagnosis and standardized AUD management.

This study had several limitations that should be acknowledged. First, all analyses were based on GBD modeled estimates, and the adopted predictive framework formed a “model-on-model” approach that accumulates inherent modeling uncertainties. Results for low-data regions, including most African, Asian, and South American countries as well as small island nations, were largely extrapolated rather than derived from primary surveillance data, which may overestimate precision and requires cautious interpretation. Additionally, GBD data may underestimate the true LCA burden in low-resource settings with incomplete vital registration and weak healthcare systems. Treating large countries such as China as single analytical units also masks substantial subnational heterogeneity in alcohol exposure and healthcare accessibility, highlighting the need for future subnational-level studies. Although the Bayesian spatiotemporal and decomposition models used in this study can generate robust population-level projections, long-term forecasting inevitably involves uncertainties. Our 2022-2050 projections were based on demographic inertia and assumed sustained current trends, without accounting for future changes in alcohol-related behaviors, public health policies, and other potential confounding factors that may alter LCA mortality trajectories. Furthermore, the findings lack direct validation against real-world epidemiological data. GBD modeling produces smoothed global epidemiological patterns that may reflect preset modeling assumptions rather than actual localized heterogeneity. Integrating granular registry-based data and conducting regional and local analyses in future research can further improve the accuracy and generalizability of burden estimates. Finally, this study could not distinguish overlapping disease etiologies due to GBD data limitations. The coexistence of multiple risk factors, such as concurrent viral hepatitis infection and hazardous alcohol consumption, could not be quantified separately, which may obscure the independent and interactive effects of different pathogenic drivers.

In conclusion, this study comprehensively analyzed the global, regional and national mortality burden of LCA, systematically revealing temporal and spatial trends and regional imbalances. Global LCA ASMR exhibited a sustained increasing trend from 1990 to 2021 and is projected to gradually stabilize and decline in the future. Targeted public health interventions, including standardized alcohol control strategies and optimized liver disease surveillance systems, are urgently needed to mitigate the rising LCA burden, particularly in high-risk regions such as Africa and the Americas.