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Introduction
Head and neck cancer (HNC) comprises a diverse group of malignancies arising from the head and neck region, including the oral cavity, pharynx, larynx, nasal cavity, and salivary glands [1]. According to GLOBOCAN 2020, HNC is the seventh most prevalent cancer globally, with annual new cases expected to reach one million by 2030 [2]. This significant burden highlights the need for a better understanding of HNC’s etiology and risk factors. Despite advances in diagnosis and treatment, prevention remains challenging due to HNC’s complex etiology, with many patients being diagnosed at advanced stages, and current therapies offering limited improvements in survival and recurrence rates [3].
Recognized risk factors for HNC include tobacco use, heavy alcohol consumption, and high-risk human papillomavirus (HPV) infection [4, 5–6]. These factors account for much of the disease burden, especially in low- and middle-income countries where smoking and alcohol use are widespread. In developed regions, HPV infection is the primary cause of oropharyngeal cancers [5]. However, approximately 20% of HNC patients lack a history of smoking or heavy drinking, indicating other, less understood factors contribute to disease development [7]. Identifying novel risk factors is crucial for developing effective preventive and therapeutic strategies, particularly for nonsmoking and nondrinking HNC patients.
Emerging evidence suggests that the GM may influence HNC development through mechanisms such as microbial balance disruption [8, 9]. Dysbiosis has been linked to the pathophysiology of several cancers, including HNC, and microbiome alterations may impact cancer risk beyond established factors [10, 11]. Additionally, dysregulated plasma protein expression has emerged as a critical factor in cancer development and progression. Recent studies across various cancer types, including breast cancer, lung cancer, prostate cancer and multiple other cancers, have explored plasma proteins as potential biomarkers and their roles in oncogenesis [12, 13, 14–15]. However, research on plasma proteins in the context of HNC remains limited. While emerging studies have started to explore the link between plasma proteins and HNC, it is still unclear whether these associations reflect direct causal effects [16, 17]. Additionally, the complex interactions between plasma proteins and the GM are not well understood. Changes in plasma protein levels may occur before clinical diagnosis, positioning them as promising biomarkers for early detection [18]. By examining plasma proteins as mediators, this study aims...