Overview: As one of the most widely used drugs in clinical practice today, aspirin has antipyretic and analgesic and cardiovascular protective effects. Decades of research have found that aspirin holds great promise in the prevention of cancer, especially colorectal cancer. Over the past few decades, numerous basic studies, clinical trials, and epidemiological surveys have found that aspirin is perhaps the most promising drug for colorectal cancer chemoprevention. The U.S. Preventive Medicine Task Force USPSTF, in 2015, recommended long-term low-dose aspirin for the prevention of colorectal cancer in patients aged 50-69 years with a clear cardiovascular risk. However, the task force also noted that long-term aspirin use can potentially lead to a number of adverse effects. I. Aspirin and colorectal cancer research history In 1988, a case-control study first found a correlation between aspirin use and a reduced risk of colorectal cancer. In 1991, the Phase II Cancer Prevention Study CPS-II, Project found a correlation between aspirin use and reduced mortality from colorectal cancer. In 1994, the Health Professionals Follow-up Study HPFS project found a correlation between aspirin use and a reduced risk of colorectal carcinoma and colorectal adenoma. In 1995, the Nurses’ Health Study NHS, project found a correlation between taking aspirin for more than 10 years and a reduced risk of colorectal cancer. In 1998, the Physicians’ Health Study PHS, Project found no correlation between taking aspirin every other day and the risk of colorectal cancer. In 2007, there was a correlation between taking aspirin and a reduced risk of developing tumors with prostaglandin oxidative cyclase 2 PTGS2, overexpression. In 2010, a long-term follow-up and Meta-analysis of a randomized controlled trial on cardiovascular disease found a correlation between aspirin use and a reduced risk of colorectal cancer. In 2011, there was a correlation between aspirin use and a reduced risk of colorectal cancer in women with high levels of soluble TNF receptor 2sTNFR2 in the blood. In 2012, there was a correlation between aspirin consumption and reduced mortality in cancer patients with PIK3CA mutations. thun et al. demonstrated that platelet inhibition is the mechanism of the anticancer effect of low-dose aspirin. In 2013, a correlation between aspirin administration and reduced risk of colorectal cancer development was found through a study of genetic variants on chromosome 8q24 in colorectal cancer cells. A randomized controlled study of women’s health with 18 years of follow-up found a reduced risk of colorectal cancer in those taking low-dose aspirin every other day. In 2014, aspirin use was associated with: 1. a reduced risk of colorectal cancer in those with high expression of the 15-hydroxyprostaglandin dehydrogenase HPGD in normal mucosal tissue; and 2. a reduced risk of adenoma in those with high levels of PGE-M, the major metabolite of prostaglandin E2, in urine. In 2015, on all cancers and cardiovascular disease prevention, researchers proposed to create a risk-benefit profile for aspirin use. Based on the cardiovascular disease risk profile, the USPSTF recommended age 50-69 years this taking low-dose aspirin for the chemoprevention of colorectal cancer. Genome-wide scan analysis confirmed that rs2965667 and rs16973225 play an important role between taking aspirin or other NSAIDs and the risk of colorectal cancer development. II. Common adverse effects of taking aspirin Based on the current literature, the most common adverse effects are non-specific gastrointestinal symptoms, including abdominal pain, dyspepsia, nausea and vomiting, while the most common serious adverse effects are gastrointestinal bleeding and occasionally intracranial hemorrhage. Bleeding adverse reactions are related to the dose taken and the age of the patient. To avoid bleeding, concomitant administration of proton pump inhibitors or H2-blockers may be clinically indicated. Aspirin is not recommended in patients with conditions such as aspirin allergy or intolerance; active gastroduodenal ulcer; comorbid bleeding disorders; recent history of gastrointestinal or intracranial bleeding; renal insufficiency; severe liver disease; and low platelet levels or thrombocytopenia. In addition, the risk and severity of bleeding adverse reactions are increased when aspirin is used in combination with anticoagulants or NSAIDs, so concomitant aspirin is not recommended for patients who have recently taken the above drugs. III. Mechanisms hypothesized for aspirin chemoprevention of colorectal cancer According to current research findings, the chemopreventive effects of aspirin are associated with several related mechanisms, including prostaglandin synthesis and metabolism in epithelial cells, inhibition of the WNT/β-catenin signaling pathway, and inactivation of platelet function and host immune response. Although high doses directly inhibit prostaglandin oxidative cyclase 2, aspirin effectively inhibits the conversion of arachidonic acid to prostaglandin E2PGE2, which activates cell membrane EP2 and thus the WNT/β-catenin signaling pathway via paracrine secretion. In addition, PGE2 can activate the cAMP and protein kinase APKA, pathways. Further, aspirin can inhibit β-catenin by inhibiting protein phosphatase 2APP2A. During colorectal tumorigenesis, PTGS2 and β-catenin are usually expressed up-regulated, causing cell proliferation and growth. Once in the nucleus, β-catenin forms a transcriptional activation complex with transcription factor 7 analogue 2TCF7L2, which activates effector genes such as MYC and PRARD. Single nucleotide polymorphism SNP, rs6983267 gene mutation or can repair the binding between the β-catenin-TCF7L2 complex and transcriptional targets. By inhibiting PTGS1, the relationship between the antiplatelet effect and low dose aspirin could be modulated. In turn, the dual antiplatelet and anti-inflammatory effects of aspirin are effective in preventing inflammation-associated tumorigenic processes, especially in individuals with high levels of inflammatory factors in the peripheral circulatory system. IV. Summary Recent clinical studies have recommended aspirin for colorectal cancer chemoprevention, and the results have initially revealed the basic mechanisms of aspirin for colorectal cancer prevention, involving several cellular signaling pathways, among which the more recognized ones are that aspirin inhibits PTGS1 from regulating TXA2 synthesis through direct inhibition of endothelial cells or platelet paracrine action, and inhibits PTGS from regulating arachidonic acid to PGE2 conversion process. In addition, aspirin also inhibits the WNT signaling pathway either directly or through downregulation of PGE2. Genetic, histological, plasma and urine biomarkers related to the above mechanisms may be important indicators to assess whether the benefits of long-term aspirin use outweigh the risks. Although promising, the adoption of relevant biomarkers and several assay characteristics collected, including specificity, sensitivity, and convenience, are important indicators to consider. For example, urine and blood-based biomarkers are more commonly used in clinical practice, but biomarker assays such as MICI or PGE-M for tumors are not as specific and can easily be confused with other inflammatory states. Histological biomarkers, such as HPGD, may be more specific than blood- and urine-based biomarkers, but the assays are usually invasive and are not recommended for use as primary prevention. Finally, the sensitivity and specificity of genetic biomarkers are mostly based on allele frequencies of population gene polymorphisms, which are easy to implement in clinical trials. Therefore, subsequent studies will focus on the discovery of reliable and valid biomarkers and explore other novel relevant cellular pathways. To achieve this goal, the ASPIRED trial program was recently initiated. Included subjects have recently undergone adenomectomy and are randomized double-blind to receive aspirin 81 mg/d, 325 mg/d, or placebo for 8 weeks. Blood, urine, colorectal biopsy, saliva, and stool samples were collected from subjects before and after taking the drug to test for cancer-related biomarkers in order to assess the cancer-preventive effect of aspirin. Other randomized controlled trials still in progress include evaluating cardiovascular adverse events in patients taking aspirin and comparing the difference in effectiveness between aspirin and fish oil. Overall, the USPSTF recommendation of aspirin for the chemoprevention of colorectal cancer has opened a new era, stimulating researchers to study the mechanisms of aspirin for cancer prevention and promoting the continuous progress of precision medicine for cancer prevention, thus benefiting an increasing number of people.