Abstract Introduction: It is important to discover and characterize new pathways and their associated gene networks in cancer cells to develop effective diagnostic and therapeutic tools. Our laboratory is focused on the impact of the RASSF1C-PIWIL1-piRNA pathway on non-small cell lung cancer (NSCLC) cell growth; and our studies have resulted in identifying specific PIWI-interacting RNAs (piRNAs) that appear to function both as oncogenes and tumor suppressors. Among the recent piRNAs identified, we found that piR-60643 targets fatty acid bind protein 5 (FABP5) in lung cancer and appears to function as a tumor suppressor. Methods: In previously published work we reported on a global microarray screen which identified potential piRNA genes in non-small lung cancer cells over-expressing RASSF1C. We were able to detect several piRNAs that are modulated by RASSF1C. The expression of specific piRNAs that appear to be down or up-regulated by RASSF1C were confirmed by RT-PCR. We evaluated the impact of selected RASSF1C-target piRNAs on lung cancer cell proliferation and migration in vitro. We also have identified both host and target genes for specific piRNAs and have used piRNA mimics to down regulate target gene expression. Results: We show that piR-60643 is down regulated by RASSF1C and seems to function as a tumor suppressor in non-small cell lung cancer cells. Consistent with this, treatment of lung cancer cells with piR-60643 mimics reduced cell proliferation and migration, supporting the idea that piR-60643 could be a new inhibitor of lung cancer cell growth and progression. To learn more about how piR-60643 may hinder lung cancer cell growth, we searched for genes that could be targeted by piR-60643. Interestingly, we identified FABP5 as a piR-60643-target gene. FABP5 is up regulated in lung tumor tissue and in tissues of other cancers and is associated with poor patient survival. FABP5 plays a key role in regulating lipid metabolism and fatty acid oxidation (FAO). FAO is critical to supply the high energy (ATP) demand of rapidly growing cancer cells and contributes to cell cycle progression, EMT, migration, and metastasis. We found that treatment of lung cancer cells with piR-60643 mimics resulted in down regulation of FABP5 expression both at the mRNA and protein levels, implying that piR-60643 could disrupt FAO-associated metabolic pathway(s) in lung cancer cells. Interestingly, we found that PIWIL1 overexpression up-regulates FABP5 expression in lung cancer cells, suggesting that the PIWIL-FABP5 gene axis may play a role in lipid metabolism/FAO. This novel finding has not been previously reported. Conclusion: Targeting FABP5 by piR-60643 could prove a novel mechanism of inhibiting lipid metabolism/FAO and impeding tumor growth and progression. As such, piR-60643 could prove to be a useful diagnostic/therapeutic tool for lung cancer. Citation Format: Yousef G. Amaar, Mark E. Reeves. PiR-60643 is a novel inhibitor of fatty acid binding protein 5 (FABP5) in lung cancer cells abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2067.
Amaar et al. (Fri,) studied this question.