NRF2-KEAP1 Signaling in Chromium-Induced Lung Carcinogenesis: Mechanistic Insights and Evidence Gaps

Hexavalent chromium [Cr(VI)] is a recognized environmental and occupational carcinogen associated with an increased risk of lung cancer. The nuclear factor erythroid 2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) pathway regulates cellular responses to oxidative and electrophilic stress and may influence cell survival following Cr(VI) exposure. Under basal conditions, KEAP1 promotes NRF2 ubiquitination and proteasomal degradation. Oxidative or electrophilic stress can impair this process, allowing NRF2 to accumulate and activate genes involved in antioxidant defense, detoxification, and cellular redox regulation, including HMOX1, NQO1, and GCLC. Although these responses can protect normal cells from acute stress, persistent NRF2 activity has also been associated with metabolic adaptation, resistance to apoptosis, and tumor-promoting phenotypes in several cancer models.However, the extent to which NRF2-KEAP1 signaling directly contributes to Cr(VI)-induced lung carcinogenesis remains incompletely established. Many studies on Cr(VI) have investigated oxidative stress, inflammation, genotoxicity, and cellular transformation. In contrast, relatively few have directly tested whether NRF2 activation is causally involved in tumor initiation or progression in chromium-exposed lung models. This review examines the relationship among Cr(VI) exposure, redox imbalance, and NRF2-KEAP1 signaling, distinguishing findings from chromium-specific experimental systems from mechanisms inferred from broader lung cancer research. It also discusses downstream processes relevant to carcinogenesis, occupational exposure, and risk assessment, as well as potential preventive or therapeutic strategies. The available evidence supports NRF2-KEAP1 signaling as an important component of the cellular response to Cr(VI)-associated stress, but further mechanistic studies are needed to establish its specific causal contribution to chromium-induced lung carcinogenesis.