There are two major histopathological types of lung cancer; small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC includes adenocarcinoma (AC) and squamous cell carcinoma (SCC). The prognosis for lung cancer patients is still poor, with a five-year survival rate of only ~19%. This is due to the fact that patients are often diagnosed late in the progression of the disease. Chemoprevention focuses on targeting early-stage carcinogenesis and is a potentially important approach to reduce the incidence of lung cancer. A major advance in the translational study of chemoprevention is the development of specific mouse models of the major subtypes of lung cancer, in which a well-characterized time course for the development of cancer can be studied and manipulated. Honokiol (HNK) is a key bioactive compound in Magnolia bark extracts and has been used for centuries in China, South Korea and Japan to treat gastrointestinal disorders, cough, anxiety, stroke and allergic diseases. HNK has high bioavailability in mice, and has shown no toxic effects in rats. Magnolia bark extract is nontoxic in both short-term and subchronic toxicity studies. Mechanistically, HNK induces apoptosis through inhibition of mitochondrial complex I, which could be a key chemopreventive mechanism. Cancer cells exhibit higher negative transmembrane potential differences across the plasma membrane and mitochondrial membranes. This facilitates cancer cell selective accumulation and retention of delocalized lipophilic cations (DLC) such as triphenylphosphonium ion (TPP+). Several mitochondria-targeted agents (MTAs) containing a TPP+ moiety attached to various bioactive molecules (e.g., HNK or Lonidame) decreased ATP levels more selectively in cancer cells than normal cells and inhibited cancer cell proliferation at nontoxic sub-micromolar levels. This provides a rationale for conjugating HNK to a targeting agent that drives it into mitochondria to dramatically increase its chemopreventive efficacy. Preliminary data demonstrates that mitochondria-targeted HNK (Mito-HNK) is a significantly more potent chemopreventive agent of lung carcinogenesis than HNK. This project will systematically determine the efficacy of Mito-HNK on two major subtypes of lung cancer: AC and SCC.