Lin, N. Y. C. | Search bioRxiv

bioRxiv2026

Cell jamming transition is regulated by mitochondrial pyruvate transport and endocytosis

Epithelial tissues undergo dynamic transitions between fluid-like collective motion and mechanically jammed states during development, injury repair, and disease progression. However, the cellular programs that drive these transitions and regulate collective behavior remain unclear. Using a controlled crowding model integrated with live-cell imaging and time-resolved multi-omics, we demonstrate that epithelial crowding triggers early metabolic changes characterized by increased mitochondrial pyruvate anaplerosis that precedes the jamming transition. Functional inhibition of mitochondrial pyruvate import is sufficient to sustain collective cell motility, impeding jamming transition in crowded cells. This unjammed state is driven by enhanced cytoskeletal remodeling and requires RhoA-myosin II activity. Mechanistically, we show that elevated cytoskeletal signaling promotes macropinocytic uptake, which serves as a required feedback loop to maintain motility. These findings identify mitochondrial pyruvate utilization as a key regulator that links metabolic remodeling to the endocytic control of epithelial fluidity.

cell biology↗

bioRxiv2026

Mechanistic Language Modeling and Oxygenated 3D Screening Reveal Berberine and Enzalutamide Synergy in Resistant Prostate Cancer

Resistance to androgen receptor inhibitors remains a primary challenge in prostate cancer treatment, yet identifying synergis-tic co-therapies is hindered by immense combinatorial search spaces and the limited interpretability of predictive computation models. Here, we developed an integrated discovery-validation axis coupling knowledge-augmented large language models with oxygen-supplemented 3D spheroid assays. By leveraging inherent model stochasticity, our framework measures the degree of consensus across independent predictions to establish a formal metric for predictive accuracy. This principle enables high-throughput assessment of complex signaling crosstalk, yielding mechanistic rationales for all predictions and defining a high-confidence zone that minimizes experimental attrition. Utilizing this approach to screen 3,592 natural products, we identified a previously unrecognized synergy between berberine and enzalutamide that re-sensitizes resistant cells. Validation confirms that berberine perturbs the PI3K/AKT/mTOR and AMPK axes, a finding consistent with the mechanistic rationales computationally derived by the framework. Integrating interpretable AI with physiologically relevant 3D screening provides a scalable methodology for the rational discovery of synergistic therapies. SignificanceIntegrating mechanistic AI with oxygenated 3D screening, we identify a novel berberine-enzalutamide synergy. This framework resolves complex signaling dependencies, providing a scalable, transparent methodology for the rational discovery of effective combination therapies.

bioengineering↗