Lip and oral cavity cancer (LOC) is one of the more common malignant tumors worldwide (1). In recent years, its incidence has shown a significant upward trend, imposing a substantial burden on global healthcare systems (2). Major risk factors for LOC include tobacco smoking, alcohol consumption, betel nut chewing, human papillomavirus (HPV) infection, and ultraviolet (UV) exposure (2). HPV infection is associated with an increased risk of oral cancer, while UV exposure primarily elevates the risk of lip cancer (3). Therefore, there is an urgent need for comprehensive global research to better understand the epidemiological patterns of LOC and to develop targeted prevention strategies aimed at reducing its incidence and mortality.

In 2020, approximately 741,300 new cancer cases globally were attributed to alcohol consumption, accounting for 4% of all newly diagnosed cancer cases that year (4). A strong association exists between heavy alcohol consumption and the risk of LOC. Studies have shown a positive correlation between alcohol consumption and the risk of oral cancer. For instance, moderate drinkers (more than 12.5 g but less than or equal to 50 g of alcohol per day) have a 1.8-fold higher risk of developing oral cancer compared to non-drinkers, while heavy drinkers (more than 50 g per day) face a fivefold increased risk (5).

Studies have shown that alcohol consumption can lead to LOC through multiple mechanisms (6–9). First, ethanol metabolism in the body produces acetaldehyde, a known carcinogen that can bind to DNA to form adducts, causing DNA damage and mutations, thereby increasing the risk of malignant transformation (10). In addition, ethanol metabolism generates large amounts of reactive oxygen species (ROS), which induce oxidative stress, lipid peroxidation, and DNA damage, while also disrupting cell signaling pathways to promote cell proliferation and metastasis (11). Ethanol can also interfere with DNA methylation and epigenetic modifications, leading to abnormal gene expression and further promoting carcinogenesis (12). Chronic heavy drinking impairs immune system function, allowing malignant cells to escape immune surveillance (13). Moreover, alcohol acts synergistically with other carcinogenic factors, such as tobacco, significantly increasing the risk of LOC (14).

This study, based on data from the Global Burden of Disease Study 2021 (GBD 2021), provides an in-depth analysis of the epidemiological characteristics of lip and oral cavity cancer attributable to high alcohol consumption (LOC-HAC). The research focuses on temporal trends in the age-standardized mortality rates (ASMR) and the age-standardized DALY rates (ASDR) associated with LOC-HAC, revealing its dynamic changes over time. Further analysis shows that gender, age, and Socio-demographic Index (SDI) significantly influence the burden of LOC across different regions and populations. In addition, the study evaluates the contributions of aging, population growth, and epidemiological changes to the LOC-HAC. It also assesses the extent of inequality among countries and projects future trends through 2045. The findings provide critical scientific evidence for the development of public health policies and initiatives aimed at reducing the burden of LOC-HAC, supporting policymakers in implementing targeted strategies to improve global public health outcomes.

The global burden of LOC-HAC has increased significantly over the past few decades, especially in regions with a low to middle SDI and Southeast Asia. In 2021, the number of DALY cases globally had risen by 90% compared to 1990, with the fastest growth occurring in low to middle SDI regions, where the percentage change was 279%. The number of death cases also showed a similar trend, with a 296% increase in low-middle SDI regions. Among the 21 GBD regions, Southeast Asia saw the most significant rise in DALY and death cases, with increases of 326 and 357%, respectively. This may be related to local lifestyle factors, such as betel nut chewing, and inadequate allocation of medical resources (29).

Although global ASDR and ASMR have declined overall, rapid increases in Southeast Asia highlight the need for strengthened health education and medical interventions. Central Europe had the highest ASDR and ASMR, indicating ongoing challenges. In the future, low-middle SDI and Southeast Asia should be prioritized, with measures such as lifestyle improvement, early screening, and optimized healthcare resource allocation to reduce the incidence and mortality of LOC-HAC (30).

From 1990 to 2021, LOC-HAC burden rose markedly in several countries, with Iran, Libya, Cape Verde, Viet Nam, and Nepal experiencing the fastest increases in DALYs and death cases. These findings suggest that these countries may face high-risk behaviors (e.g., smoking, alcohol use) and limited healthcare resources. In Iran, major health system reforms and improved reporting may have contributed to the substantial increases. Some data may also have been influenced by exceptional events such as policy changes or targeted health interventions.

In 2021, DALYs and death cases in males were significantly higher than in females, and both increased with age. Male DALYs peaked at 55–59 years, while female DALYs peaked at 60–64 years. These differences may be due to variations in survival, exposure levels, and diagnostic practices between sexes. Men may be more likely to engage in high-risk behaviors earlier, while women may experience later exposures. Additionally, differences in diagnosis may account for the variation in peak ages.

Although SDI was positively correlated with ASDR and ASMR, both declined when SDI exceeded 0.75. This may be explained by better healthcare access, preventive strategies, and changing alcohol consumption patterns in high-SDI regions. Comprehensive health education, early detection, and effective public health policies in these regions may have reduced the burden of LOC-HAC.

Over the past 32 years, the global disease burden of LOC-HAC has increased significantly, driven mainly by population aging and population growth, while epidemiological changes have had a certain mitigating effect. In addition, global health inequality has become more pronounced between countries at different levels of socio-economic development, with the gap in disease burden between high SDI regions and low SDI regions gradually widening, and high SDI regions still bearing a heavier burden. This means that the improvement in health status in high SDI regions may be faster than that in low SDI regions, or the deterioration in health status in low SDI regions may be more rapid. Therefore, it suggests that policymakers need to pay more attention to low SDI regions in terms of resource allocation and health interventions to narrow the health gap.

Assuming current alcohol consumption trends and policies remain unchanged, forecasts suggest that from 2022 to 2045, DALYs and death cases among males will rise substantially, while increases among females will be modest. ASDR and ASMR are expected to remain relatively stable but consistently higher in males. This underscores the need for interventions targeting high-risk behaviors in men while continuing to address women’s health needs.

Extensive evidence has established alcohol and its metabolite acetaldehyde as Group 1 carcinogens, acting through multiple mechanisms (31). Ethanol metabolism produces acetaldehyde, which damages DNA and impairs repair pathways, and generates ROS that drive oxidative stress and genomic instability (32). Alcohol also alters hormone levels, suppresses immune surveillance, and enhances the carcinogenicity of tobacco and other agents (33). Together, these pathways markedly increase the risk of several cancers, including oral cancer.

Several policy interventions have proven effective in substantially reducing alcohol consumption (34). For instance, increasing taxation on alcoholic beverages has been shown to decrease consumption, with particularly strong effects observed among low-income populations and younger individuals. Similarly, the implementation of minimum unit pricing policies can discourage the excessive intake of inexpensive alcoholic products, thereby mitigating harmful drinking behaviors (34, 35). Moreover, restricting the hours and days of alcohol sales and limiting outlet density have demonstrated efficacy in reducing alcohol availability, leading to lower consumption and associated health risks (36). Given the considerable disease burden of LOC, a multifaceted approach is warranted. In low-middle SDI regions and in Southeast Asia, health education campaigns should be prioritized to improve public awareness of high-risk behaviors, including tobacco use, alcohol consumption, and betel quid chewing, and to promote healthier lifestyle choices. The establishment of early screening programs for LOC is also crucial, particularly in high-incidence countries and among older populations, to enhance early detection and improve treatment outcomes. In parallel, optimizing the allocation of healthcare resources by expanding treatment facilities and increasing the availability of trained specialists in resource-limited settings will be essential. Furthermore, the development and enforcement of alcohol- and tobacco-control policies can reduce the prevalence of high-risk behaviors, with tailored interventions targeting men, who remain disproportionately affected. Finally, strengthening international collaboration to share best practices and coordinate responses will be vital, with a focus on regions and populations carrying the heaviest burden, in order to achieve meaningful reductions in the incidence and mortality of LOC.

This study has some limitations. First, GBD data quality and representativeness in low- and middle-income countries may be limited due to less robust data collection and reporting systems. Second, while this study systematically analyzed epidemiological changes across regions and countries, it did not explore subpopulations (e.g., provincial, urban–rural differences). Third, LOC-HAC may suffer from underreporting or misclassification. Fourth, the COVID-19 pandemic may have affected data collection and reporting for 2021, leading to bias or incompleteness.

Based on GBD 2021 data, this study analyzed global trends in LOC-HAC burden from 1990 to 2021. The results show significant increases in DALYs and death cases, with the greatest rises in low-middle SDI regions and Southeast Asia. Males had higher DALYs cases than females, with peaks at ages 55–59 for males and 60–64 for females. Substantial global health inequalities were observed, with widening absolute differences between the highest and lowest SDI regions. Forecasts suggest that from 2022 to 2045, DALYs and death cases will increase significantly in males, while females will show slower increases. This study recommends prioritizing low-middle SDI and Southeast Asia by promoting healthy lifestyles, strengthening early screening, and optimizing healthcare resource allocation to reduce the incidence and mortality of LOC-HAC.