Bladder cancer (BC) is the most common neoplasm of the urinary system, which is associated with high morbidity and mortality rates. Globally, 573 278 new cases and 212 536 related deaths were reported in 2020.1 Urothelial carcinoma (UC) is the most frequent histologic type among BC, with 75% non-muscle-invasive BCs (NMIBCs) and 25% MIBCs. The definition of UC is the urothelial-origin neoplastic cells that invade the basement membrane, lamina propria, or deeper. NMIBCs frequently recur and progress to MIBCs,2 which are usually associated with lower 5-year survival rates, cancer progression, and metastasis.3 Kinds of driver events are aberrantly activated in UC. In this issue of Clinical and Translational Medicine, Ikeda et al. demonstrated that Mint3 is responsible for the poor prognosis of UC, as both Mint3 deletion and inhibition would hinder tumour development.4 Mechanistically, Mint3 is a positive regulator of hypoxia-inducible factor-1 (HIF-1), which is highly related to diversified oncogenic processes in UC cells, such as angiogenesis, glycolysis, motility, and invasion (Figure 1). Mutations of two genes, namely FGFR3 and TP53, are generally recognized in the pathological process of UC. The former type mainly comprises papillary and low-grade tumours arising from localized and flat urothelial hyperplasia and accompanied by only a single or few genetic alterations.5 Different from FGFR3-mutated UC, the TP53 mutation-related ones are defined as essential carcinoma in situ (CIS) developed from severe dysplasia and consist of non-papillary and high-grade tumours. The TP53-mutated UC is considerably more lethal due to its high rate of progression and its association with multiple chromosomal abnormalities and muscle-invasive tumours.6 Meanwhile, certain tumours with both FGFR3 and TP53 gene mutations were observed and confirmed with non-muscle invasion but similar molecular alterations with CIS, which results in a poor prognosis.7 The protocol of UC treatment was built 20 years ago and has proved to be efficient in overall survival benefits ever since.8 However, this longstanding paradigm has been challenged and supplemented by new cancer therapies that emerged recently, including immuno-checkpoint inhibitors,9 antibody-drug conjugates (ADCs),10 and novel targeted drugs.11 In general, platinum-based chemotherapy is the recommended first-line standard therapy for suitable patients, while cisplatin is preferred to carboplatin. Immuno-checkpoint treatment could be an alternative if the PD-L1 status of the patient were positive. Immunotherapy is a commonly used second-line treatment, but some could be integrated into first-line chemotherapy, which is appropriate for patients applying platinum-based therapies. Meanwhile, several trials of Nectin-4 targeted ADC and FGFR inhibitors applying in UC solely or combined with different chemotherapies are undergoing. The updated therapies and drugs are listed in Table 1. Among all biological pathways, the MAPK/PI3K-HIF1 signalling pathway was proved to contribute significantly to the pathologies of UC by participating in multiple UC-associated tumourigeneses and metastasis processes, including tumour cell proliferation, apoptosis, glycolysis, and tumour angiogenesis.23 HIF-1 is a member of the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family and a heterodimer consisting of HIF-1α and HIF-1β subunits. The former degrades under nonmonic conditions but is stable under hypoxic conditions and functions as a master transcriptional regulator of the adaptive response to hypoxia, whereas the latter is expressed constitutively.24 HIF-1α is wildly involved in numerous types of cancers. Significant associations between HIF-1α overexpression and patient mortality have been demonstrated in cancers of the brain, breast, cervix, oropharynx, ovary, and uterus.25 In this case, HIF-1α is often upregulated in both early and advanced stages of UC, associated with poor survival rates. Several studies delineated that HIF-1α activation predicts poor prognosis, accelerates tumour growth and promotes radiation therapy resistance by upregulating multiple carcinogenic genes, while its knockout quenches the promoting roles.25-27 Although it seems promising to develop a HIF-1-targeted drug as the ideal strategy of UC therapy, difficulties arose, and no HIF-1 inhibitor is clinically available to date as a result, despite countless efforts have been applied during the last decade in search of potential HIF-1 inhibitors.23 Another strategy for the inhibition of HIF-1 is to divert attention to its regulators. Along with illustrious signalling translation points like PI3K and mTOR, Mint3 is a newly discovered HIF-1 activator. It exhibits oncogenic functions in multiple cancer cell lines.28, 29 Although the other two members of the X11 protein family, namely Mint1 and Mint2, are neuron proteins, Munc18-1-interacting protein 3 (Mint3/X11γ/APBA3) is ubiquitously expressed and generally upregulated in tumours.30 The transcriptional activity of HIF-1α is typically regulated by factor inhibiting HIF-1 (FIH-1), an asparaginyl hydroxylase functioning as an interrupter preventing the binding of HIF-1α and its transcriptional co-factor p300/CBP by modifying the Asn803 residue of HIF-1α. Mint3 was demonstrated to be capable of competitively binding to FIH-1 through the N-terminal region, thus promoting the activation of HIF-1α.31 The protein-protein interaction between Mint3 and FIH1 is also regarded as the key regulatory mechanism of the Warburg effect, which is one of the phenomena that are considered to play a pivotal role in the survival and proliferation of tumour cells.30 It is also proved that the Mint3 deletion would lead to the inhibition of tumour growth and enhancement of the chemosensitivity in kinds of malignancies, including breast cancer, pancreatic cancer, lung cancer, and fibrosarcoma.29, 32-34 Unlike the concentration and fervency in research of HIF-1 inhibitor discovery, there are only a few acknowledged antagonists for Mint3 due to the unclearness of both its regulating mechanism and binding mode with FIH-1. Inspiringly, recent works focusing on the protein structure have revealed the biological basis and identified amino acids 78 to 88 of Mint3 as the essential binding region with FIH-1.30 These findings would more than likely accelerate the development of novel Mint3-targeted drugs for UC. Besides the oncogenic role of the Mint3-HIF-1 axis in UC, Ikeda's work also highlighted the antagonistic function of the Mint3-targeted drug, naphthofluorescein, against chemoresistance. This could bring the current platinum-based chemotherapy reasonable countermeasures for the drug resistance caused by long-term chemotherapies, especially in treatments for advanced cancers. However, it still requires abundant investigations into the effectiveness and ineluctable side effect of Mint3 inhibitors to materialize the clinical vision, given the tumour microenvironment heterogeneity and the complexity of biological processes regulated by HIF-1. We acknowledge the technical support from Core utilities of cancer genomics and pathobiology of the department of anatomical and cellular pathology, The Chinese University of Hong Kong. The authors declare that they have no conflict of interest.