Exploring the Association Between Gastroesophageal Reflux and Temporomandibular Joint Disorder in European Populations: A Bidirectional Mendelian Randomization Analysis.

INTRODUCTION AND AIMS: Gastroesophageal reflux disease (GERD) and temporomandibular joint disorder (TMD) are relatively common conditions with a potential causal relationship. This study aims to investigate the possible causal relationship between GERD and TMD through bidirectional Mendelian randomization analysis. METHODS: Using data from large GWAS databases, we conducted bidirectional Mendelian randomization analyses to investigate the potential causal link between GERD and TMD. Instrumental variables were selected from the IEU platform, comprising 129,080 GERD cases and 473,524 controls from the UK Biobank. TMD data from the FinnGen project included 6,314 cases and 222,498 controls. RESULTS: The forward MR analysis suggested that GERD may increase the risk of TMD (OR = 1.47, 95% CI: 1.20-1.81, P = 2e-4). The Weighted Median method also yielded significant results (OR = 1.53, 95% CI: 1.14-2.04, P = 4.1e-3). However, the reverse MR analysis did not reveal a significant association between TMD and GERD (OR = 1.02, 95% CI: 0.98-1.05, P = .33). CONCLUSION: This study, employing MR analysis, provides initial evidence supporting a potential causal relationship between GERD and TMD. The findings contribute to a better understanding of the relationship between these two conditions and offer insights for future clinical investigations. CLINICAL RELEVANCE: The findings of this study hold potential clinical significance in guiding early management strategies for GERD, reducing the incidence of TMD, and optimizing healthcare resource allocation, thereby improving patient quality of life. Further clinical studies are warranted to validate these findings and explore underlying mechanisms.

BRD4 inhibitors broadly promote erastin-induced ferroptosis in different cell lines by targeting ROS and FSP1.

Ferroptosis, an iron-dependent form of programmed cell death, is a promising strategy for cancer treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic reader and a promising target for cancer therapeutics. However, the role of BRD4 in ferroptosis is controversial and the value of the interaction between BRD4 inhibitors and ferroptosis inducers remains to be explored. Here, we found that BRD4 inhibition greatly enhanced erastin-induced ferroptosis in different types of cells, including HEK293T, HeLa, HepG2, RKO, and PC3 cell lines. Knocking down BRD4 in HEK293T and HeLa cells also promoted erastin-induced cell death. BRD4 inhibition by JQ-1 and I-BET-762 or BRD4 knockdown resulted in substantial accumulation of reactive oxygen species (ROS) in both HEK293T and HeLa cells. The effect of BRD4 inhibition on ferroptosis-associated genes varied in different cells. After using BRD4 inhibitors, the expression of FTH1, Nrf2, and GPX4 increased in HEK293T cells, while the levels of VDAC2, VDAC3, and FSP1 decreased. In HeLa cells, the expression of FTH1, VDAC2, VDAC3, Nrf2, GPX4, and FSP1 was reduced upon treatment with JQ-1 and I-BET-762. Consistently, the level of FSP1 was greatly reduced in HEK293T and HeLa cells with stable BRD4 knockdown compared to control cells. Furthermore, ChIP-sequencing data showed that BRD4 bound to the promoter of FSP1, but the BRD4 binding was greatly reduced upon JQ-1 treatment. Our results suggest that ROS accumulation and FSP1 downregulation are common mechanisms underlying increased ferroptosis with BRD4 inhibitors. Thus, BRD4 inhibitors might be more effective in combination with ferroptosis inducers, especially in FSP1-dependent cancer cells.