TY - JOUR T1 - An unconventional cancer-promoting function of methamphetamine in hepatocellular carcinoma JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201660 VL - 6 IS - 3 SP - e202201660 AU - Zizhen Si AU - GuanJun Yang AU - Xidi Wang AU - Zhaoying Yu AU - Qian Pang AU - Shuangshuang Zhang AU - Liyin Qian AU - Yuer Ruan AU - Jing Huang AU - Liu Yu Y1 - 2023/03/01 UR - https://www.life-science-alliance.org/content/6/3/e202201660.abstract N2 - For the past decade, the prevalence and mortality of methamphetamine (METH) use have doubled, suggesting that METH use could be the next substance use crisis worldwide. Ingested METH is transformed into other products in the liver, a major metabolic organ. Studies have revealed that METH causes deleterious inflammatory response, oxidative stress, and extensive DNA damage. These pathological damages are driving factors of hepatocellular carcinoma (HCC). Nonetheless, the potential role of METH in HCC and the underlying mechanisms remain unknown. Herein, we found a higher HCC incidence in METH abusers. METH promoted cellular proliferation, migration, and invasion in two human-derived HCC cells. Consistently, METH uptake promoted HCC progression in a xenograft mouse model. Mechanistically, METH exposure induced ROS production, which activated the Ras/MEK/ERK signaling pathway. Clearance of ROS by NAC suppressed METH-induced activation of Ras/ERK1/2 pathways, leading to arrest of HCC xenograft formation in nude mice. To the best of our knowledge, this is the first study to substantiate that METH promotes HCC progression and inhibition of ROS may reverse this process. ER -