Oral submucous fibrosis (OSMF) is an oral potential malignant disorder (OPMD) which impacts 1-2% of the adult population (Rao & Villa, 2020). Its histopathological characteristics include inflammatory cell infiltration at the juxta-epithelial region associated with fibrosis and concomitant diminution of epithelium resulting in mucosal rigidity and impaired function (Rao & Villa, 2020; Bhatt P et al., 2019). An essential contributor to the etiology of OSMF is the chewing of areca quid (Wollina et al., 2015). Mass addiction to this deleterious habit stems from its easy access, low cost and effective marketing tactics, particularly among populations in Southeast Asia and the Indian subcontinent (Wazir et al., 2015). In accordance with the World Health Organization (WHO), the rate of malignant transformation in OSMF ranges from 7–30% (Arakeri & Brennan, 2013). Investigating the existence of molecular markers has been a primary domain of research that might be utilized to detect OSMF instances with a high risk of progression into malignancy.

Hypoxia is the primary trigger for the potential malignant transformation which is mediated by multiple proteins like HIF, BNIP3, PDK1, and GLUT1 along with markers like CAIX, LDH-5, MCT1, and MCT4 (Tsai et al., 2015). A multitude of studies enumerate the importance of hypoxia inducible factor - 1/2 alpha (HIF-1/2α) in OSMF (Tsai et al., 2015, Tilakaratne et al., 2008, Joseph et al., 2020). HIF-1/2α is an oxygen-sensitive transcriptional activator that exists as a heterodimer composed of α and β subunits (Pereira et al., 2020). In hypoxic situations, HIF-1/2α interacts with hypoxia-responsive elements within the nucleus (Sharma et al., 2022). It is also crucial in upregulating the genes that promote angiogenesis, iron metabolism, glucose metabolism and cell proliferation/survival of cells from normoxia to hypoxia (Ziello et al., 2007). An overview of the entire literature mainly asserts the synergistic relation between HIF-1α and OSMF while a single study by Joseph et al., 2020 claiming the importance of HIF-2α (Tsai et al., 2015, Tilakaratne et al., 2008, Joseph et al., 2020, Pereira et al., 2020; Sharma et al., 2022). Regardless, there is limited application of HIF-1/2α targeted therapies which thereby highlights the lacunae in the existing literature.

Owing to the high malignant transformation rate of OSMF into malignancy it is imperative to identify high-risk cases and subsequently adopt effective treatment modalities eventually clarifying the unresolved pathophysiology of OSMF (Hosagadde et al., 2016). Thus, this systematic review and meta-analysis were intended to delve into the intricate role of HIF-1/2α in the progression and malignant transformation of OSMF in order to establish its significance in future diagnostic and therapeutic approaches for alleviating fibrotic changes as well as to halt disease progression.