Esophageal cancer represents a global health concern, with an annual incidence of over 600,000 newly diagnosed cases, accounting for over 3% of all cancer cases. Esophageal squamous cell carcinoma (ESCC) is mainly distributed in East Asia and is the major type of esophageal cancer occurred in China. However, the 5-year survival rate for ESCC is less than 20% due to recurrence, acquired drug resistance, and the lack of actional targets. Therefore, understand the etiology and pathogenesis of ESCC and screen chemopreventive drugs are urgently needed to improve the survival rate of ESCC patients. Exposure to harmful external stimuli, such as hot foods, chemicals, and others often results in cellular stress responses, and contributes to cancer. Under the 42℃ and 4NQO stimulus, p38/ERK signaling pathway was activated during ESCC progression. Long-chain-fatty-acid--CoA ligase 4 (ACSL4), which is a fatty acid metabolic enzyme, can be phosphorylated by p38, resulting in increased production of myristoyl-CoA, then promotes Src myristoylation and activates ERK. Epigenetic regulation is accomplished through the concerted effort of histone writers, readers, and erasers. Alterations in epigenetic modulators are critical to cancer development and prognosis. BRD4, as a “chromatin reader” protein, its interaction with TP73 facilitated the binding of BRD4 complex to the promoter region of RCC2, and subsequently modulated RCC2 transcription. Genetic or pharmacological inhibition of BRD4 suppressed ESCC cell proliferation. Chemoprevention is a promising strategy to prevent the recurrence of cancer, and screening the library of drugs already approved by the FDA to discover drugs for this purpose may be an effective shortcut. Indomethacin as an anti-inflammatory drug, inhibits patient-derived xenograft tumor growth and recurrence by targeting integrin αvβ3. And Arbidol as a broad-spectrum antiviral compound, inhibits ESCC growth through suppressing ataxia telangiectasia and Rad3-related protein kinase.