Update information. Cross-linking Mass Spectrometry (XL-MS) is a powerful tool for examining protein structures and interactions. Nevertheless, anal-ysis of low-abundance cross-linked peptides is often limited in data-dependent acquisition (DDA) mode due to its semistochastic nature. To address this issue, we introduced a workflow called 4D-diaXLMS, representing the first-ever application of four-dimensional data-independent acquisition for proteome-wide cross-linking analysis.