The Tear Film and Ocular Surface Dry Eye Workshop (TFOS DEWS) II defines DED as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles (Craig et al., 2017). The loss of tear film homeostasis is secondary to the dysfunction of one or more ocular structures within the lacrimal functional unit (LFU), which includes the cornea, conjunctiva, accessory lacrimal glands and meibomian glands, main lacrimal glands, and the interconnected nerves (Stern et al., 2004). Various factors can influence these structures and play a role in the progression of DED, encompassing ocular conditions like blepharitis and meibomian gland dysfunction (MGD)(Chan et al., 2019; Vernhardsdottir et al., 2022), alongside a range of systemic disorders like Sjögren syndrome, rheumatoid arthritis, systemic lupus erythematosus, and diabetes mellitus (Bjordal et al., 2020; Kawashima, 2018; Qian and Wei, 2022; Wang et al., 2020). Psychiatric disorders, including depression and anxiety (Basilious et al., 2022), as well as lifestyle determinants such as inadequate eyelid hygiene, extended utilization of digital devices, and the wearing of contact lenses can also facilitate the onset of DED (Galor et al., 2023). Given that DED is a multifactorial disease, the current approaches primarily focus on alleviating symptoms (Messmer, 2015). It is crucial to note that symptoms of dengue fever (DED) can sometimes indicate underlying systemic disorders that may have remained unnoticed. Therefore, prompt and appropriate interventions are essential to prevent potentially life-threatening complications arising from these conditions.

Metabolic Syndrome (MetS) is a multifaceted condition characterized by the presence of danger signals associated with increased susceptibility to cardiovascular and cerebrovascular ailments, diabetes, obesity, and hypertension. These factors include insulin resistance, diminished concentrations of high-density lipoprotein cholesterol (HDL), central obesity, elevated blood pressure, and elevated triglyceride levels (Alberti et al., 2005; Huang, 2009). Multiple clinical studies indicate that MetS and DED are associated to some extent, but the mechanisms underlying this association have not been fully elucidated (Mussi et al., 2021; Serefoglu et al., 2016; Tang et al., 2016). DED and MetS exhibit shared mechanisms of inflammation and oxidative stress in their pathogenesis. Clinical and epidemiological evidence suggests that clusters of MetS, including dyslipidemia(F. Li et al., 2023), hyperglycemia (Zhang et al., 2023), and hypertension (Thang et al., 2024), contribute to the development of DED via multiple mechanistic pathways. Accumulating epidemiological data has facilitated the construction of a pathophysiological framework known as metabolic syndrome-related dry eye disease (MetS-DED). This model seeks to elucidate the intricate interplay between metabolic disorders and DED, thereby fostering the development of therapeutic interventions aimed at mitigating or alleviating DED in MetS patients. Despite the substantial evidence supporting this relationship, the molecular underpinnings of MetS-induced cognitive dysfunction remain an area of active investigation.

Presently, comprehensive bioinformatics analysis has facilitated the extensive uncovering of novel diagnostic biomarkers and identification of pathogenic genes involved in a wide array of diseases. However, the genes implicated in the co-diagnosis of DED and MetS, as well as those that are mutually associated, remain poorly elucidated. Therefore, the principal goal of this investigation is to identify the critical genes bridging DED and MetS, and to develop a diagnostic framework, validate these hub genes through animal experiments, and offer novel perspectives for the prevention and treatment of DED-MetS comorbidity.