We are performing a small RNA seq experiment and had one sample over cluster by about 5-fold compared to the rest of the libraries. With the intention of using DESeq2 after processing the data, would you suggest subsampling to match the rest of the sample depths, or will DESeq2 handle the scaling fine to keep the sample from becoming an outlier? I couldn't find this question answered elsewhere, but maybe my search terms were lacking. Thanks in advance!

Basically, no, you shouldn’t subsample and there’s nothing special you need to do here.