We speculate that the elucidation of the key mechanisms driving eNAMPT secretion/release allow for targeting of secretory pathways and identification of novel therapeutic approaches to mitigate eNAMPT/TLR4 signaling and innate immune-mediated enhanced severity of inflammatory, fibrotic and neoplastic diseases, a major global unmet medical need. Here, TLR4 is linked to neoplasm.