Mechanistic Insights into Flavonoid Hepatoprotection in Antitubercular Drug-Induced Hepatotoxicity: A Systematic Review of Preclinical Studies

Abstract

Antitubercular Drug-Induced Hepatic Dysfunction (ATDIHD) is a major challenge in treating tuberculosis, especially when using first-line drugs. Research shows that oxidative stress plays a central role in liver injury. Further, it triggers inflammatory and apoptotic pathways in liver cells. As a result, ATDIHD develops through an interplay between these pathways. Flavonoids can protect the liver from the damaging effects of TB medication by exerting antioxidant and anti-inflammatory effects. The study aimed to systematically evaluate preclinical evidence on the hepatoprotective effects of flavonoids and their mechanisms in ATDIHD. Data were collected from PubMed, Scopus, Google Scholar, and ScienceDirect to screen studies evaluating the protective effects of flavonoids against ATDIHD published up to 18 November 2025. In this review, 38 studies were included. Most were preclinical, with only a few being clinical studies. Silymarin, quercetin, naringenin, and catechin showed protection against hepatic damage. Among these compounds, silymarin has been widely researched and supported by both preclinical and clinical studies. Quercetin has also been found to reduce liver toxicity by activating the Nuclear Factor Erythroid 2-related factor 2 (Nrf2) pathway and blocking Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling. This review demonstrates that flavonoids may reduce hepatotoxicity by modulating oxidative stress, inflammatory responses, and apoptotic pathways, indicating their potential role as adjuncts to antitubercular therapy. Most of the available data, however, come from different preclinical models that use varied study designs, doses, and outcome parameters. This makes it difficult to directly apply the findings in clinical practice. Flavonoids show promising hepatoprotective effects in preclinical models of antitubercular drug-induced hepatic dysfunction. Further well-designed clinical studies are needed to confirm their effectiveness and safety as an add-on therapy.