Sema5a, or Semaphorin-5A, is a multifunctional protein. It acts as a bifunctional guidance cue in neurons, with its interactions with heparan sulfate (HS) and chondroitin sulfate (CS) glycosaminoglycans (GAGs) mediating attractive and inhibitory effects on neuronal growth respectively [2]. It is also involved in various biological processes related to diseases. For example, it may be related to pathways like ECM-receptor interaction in gastric cancer [3].

In pancreatic adenocarcinoma (PDAC), M2 type tumor-associated macrophages (TAMs)-derived Sema5A binds to its receptor PLXNB3 expressed on tumor cells. Using intrasplenic injection mouse models and Kras G12D/Trp53 R172H/Pdx1-Cre (KPC) mouse models, researchers found that this axis promotes tumor cell proliferation and outgrowth by enhancing the Warburg effect, which is a key process in cancer metabolism [1].

In rheumatoid arthritis, Sema5A expression is increased in patients compared to healthy controls. In a collagen-induced arthritis (CIA) mouse model, Sema5A-mAbs significantly attenuated joint injury and the inflammatory response, and the TSP1 domain of Sema5A was shown to be essential for pannus formation [4].

In summary, Sema5a is crucial in neuronal growth guidance and is involved in disease-related processes such as cancer metastasis and arthritis development. Mouse models, like those used in PDAC and RA studies, have been instrumental in revealing its role in these specific disease conditions, providing insights into potential therapeutic targets.