Fibroblast-derived HSD11B1 deficiency drives lung cancer in never-smokers through steroid metabolic imbalance

Lung cancer is one of the leading causes of cancer-related death worldwide, yet its development in people who have never smoked remains poorly understood. This form of cancer is thought to differ from smoking-related disease in both clinical behavior and molecular features, but its causes are still unclear. Growing evidence suggests that changes in the way cells process and regulate metabolites may play an important role. Here we show that a specific steroid-regulating enzyme, HSD11B1, acts as a protective factor against lung cancer in people who have never smoked. Using genetic analyses, single-cell profiling and functional studies, we found that loss of this enzyme in fibroblasts alters the local balance of steroid metabolites, which in turn promotes the transformation and growth of lung epithelial cells. These findings identify fibroblast-derived HSD11B1 as a gatekeeper of metabolic balance in the lung, with its loss linked to early disease progression and poorer outcomes in patients. By uncovering a metabolic mechanism that is distinct from smoking-related pathways, this work provides fresh insight into why never-smokers develop lung cancer and suggests potential new avenues for prevention and treatment.