A Roadmap for Improving Reliability and Data Sharing in Crosslinking Mass Spectrometry.

Crosslinking mass spectrometry (MS) can uncover protein-protein interactions and provide structural information on proteins in their native cellular environments. Despite its promise, the field remains hampered by inconsistent data formats, variable approaches to error control, and insufficient interoperability with global data repositories. Recent advances, especially in false discovery rate models and pipeline benchmarking, show that crosslinking MS data can reach a reliability that matches the demand of integrative structural biology. To drive meaningful progress, however, the community must agree on error estimation, open data formats, and streamlined repository submissions. This perspective highlights these challenges, clarifies remaining barriers, and frames practical next steps. Successful field harmonization will enhance the acceptance of crosslinking MS in the broader biological community and is critical for the dependability of the data, no matter where it is produced.