Virus infections such as HIV/AIDS and SARS-CoV-2/COVID-19 sicken hundreds of millions of people. The current multiple pandemics have caused unprecedented levels of stress and other life disruptions, which exacerbate substance use disorders, increasing side effects of antiviral drugs and interfering with recovery of individuals suffering from virus infections. Antivirals such as remdesivir, molnupiravir, ritonavir, nirmatrelvir, tenofovir, and darunavir are commonly used to inhibit replication or cell entry for HIV and SARS-CoV-2, thereby inhibiting viral infections. However, some antivirals such as ritonavir of current regimens, especially in combination with other drugs or substance alcohol use, often induced liver injuries causing serious complications. Recently, we have found that remdesivir, ritonavir, and alcohol induce cellular organelle stress, especially endoplasmic reticulum (ER) stress, which is well established not only to cause hepatic cell death but also to compromise immune response leading to a spectrum of liver diseases in a variety of animal models as well as in human patients. Most recently, we discovered with next-generation RNA sequencing that a host protease, RCE1 is a potential off- target of the antiviral drugs. The substrates of RCE1 are limited to a few Rab small GTPase proteins (Rab proteins) with a CaaX motif, which are consequently reduced in the presence of anti-HIV or anti- COVID-19 drugs and reduced much more in drug and alcohol combinations. Because the Rab proteins regulate ER-Golgi trafficking that is essential for cellular organellar homeostasis in the liver, we hypothesize that the antiviral drugs inhibit the host RCE-Rab proteins and induce organelle stress responses that leads to fatty liver injury, and alcohol consumption under stress conditions (e.g., suffering from COVID-19 or frequent quarantine) worsens the drug-induced liver complications. We propose to investigate the pathogenic mechanisms of the RCE-Rab pathway in the antiviral-induced organelle stress and explore pharmaceutical and genetic solutions to mitigate the antiviral drug-induced hepatic injury. Our specific aims are to: (1) validate the mechanistic link of the RCE-Rab pathway with anti-HIV drug and alcohol-induced organelle stress and liver injury, (2) verify whether emerging anti- coronavirus drugs and/or alcohol consumption inhibit the RCE-Rab pathway and induce organelle stress in the liver, (3) explore pharmaceutical and genetic solutions to mitigate the antiviral drug- induced liver injury via testing prophylactic effects of enhanced expression of Rab proteins that compensate the consequence of the antiviral-inhibited host protease, and testing effects of unique enzyme nano-particles that facilitate alcohol removal. Our long-term objectives are to unravel specific pathogenic mechanisms underlying side effects of antivirals so that to improve/modify current antiviral drugs for a better care of the AIDS patients suffering from HIV and SAR...