Mechanistic Rationale for the Superiority of N-Acetylcysteine over Dexamethasone in Post-Embolization Syndrome: A Combined Clinical, Pharmacokinetic, DFT and Docking Investigation

Background: Hepatocellular carcinoma (HCC) is a major health concern in Thailand, with most patients diagnosed at an intermediate stage. While transarterial chemoembolization (TACE) is a standard treatment for HCC, post-embolization syndrome (PES) remains a frequent and debilitating complication. Both Dexamethasone (DEXA) and N-acetylcysteine (NAC) have shown promise in alleviating PES symptoms, yet no head-to-head comparative studies exist to determine which is more effective. Aim: This trial aimed to directly compare the effectiveness of NAC versus DEXA in preventing PES in patients with intermediate-stage HCC undergoing conventional TACE (cTACE). The study seeks to address the gap in current literature and provide evidence on the superior intervention for mitigating PES after TACE. Methods: A prospective, randomized, double-masked controlled study was conducted at two tertiary centers in Thailand from November 2024 to April 2025. A total of 56 patients (ages 18-70) with intermediate-stage HCC were randomized in a 1:1 ratio to receive either NAC or DEXA. The NAC protocol included a loading dose of 150 mg/kg/h followed by a continuous infusion, while DEXA was administered as a single 8 mg IV dose one hour before TACE. The primary endpoint was the incidence of PES within 48 hours, evaluated using the South West Oncology Group toxicity grading and Common Terminology Criteria for Adverse Events (CTCAE). Secondary endpoints included liver decompensation and changes in the albumin-bilirubin (ALBI) score. Results: NAC significantly reduced the incidence of PES (32.1%) compared to DEXA (64.3%), with an adjusted odds ratio = 0.17 (95% CI: 0.03–0.87; P = 0.033). Only 3.6% of patients developed liver decompensation, and there was no significant difference in ALBI score deterioration between the two groups. A computational study using Density Functional Theory (DFT) and Molecular Docking was conducted to examine the molecular mechanisms of action for both drugs. The study revealed that NAC targets the Keap1/Nrf2 pathway, mitigating oxidative stress, while DEXA binds to the Glucocorticoid Receptor (GR) to suppress inflammation. SwissADME predicted favorable pharmacokinetic properties for both drugs, with NAC showing enhanced reactivity towards oxidative stress. Conclusion: In patients with intermediate-stage HCC undergoing cTACE, NAC significantly reduced the incidence of PES compared to DEXA. The clinical findings were supported by computational studies demonstrating NAC’s unique ability to mitigate oxidative stress via the Nrf2 pathway. NAC emerges as a more effective prophylactic strategy for PES prevention in Barcelona Clinic Liver Cancer (BCLC) stage B patients with preserved hepatic function. The computational insights into NAC’s mechanism further bolster the clinical efficacy, making it a promising adjunct in the treatment of PES.