# Mitophagy suppression via lncRNA H19 silencing: a novel strategy to overcome cisplatin resistance in lung adenocarcinoma

## TL;DR

This study shows that silencing the lncRNA H19 in lung cancer cells can reverse resistance to the chemotherapy drug cisplatin by inhibiting mitophagy.

## Contribution

The novel finding is that H19 translocation to mitochondria mediates cisplatin resistance, and its silencing restores drug sensitivity by suppressing mitophagy.

## Key findings

- H19 is upregulated and translocates to mitochondria in cisplatin-resistant lung cancer cells.
- Silencing H19 impairs mitophagy, promotes apoptosis, and restores cisplatin sensitivity in resistant cells.
- H19 overexpression in parental cells does not significantly affect mitophagy or drug resistance.

## Abstract

Cisplatin (DDP) resistance substantially compromises treatment efficacy in lung adenocarcinoma (LUAD). This study investigates the role of mitochondrial long non-coding RNA (lncRNA) H19 in mediating DDP resistance. High-throughput sequencing and RT-qPCR analyses revealed pronounced H19 upregulation in DDP-resistant A549 (A549/DDP) cells relative to parental A549 cells. Subcellular localization studies indicated that H19 is primarily nuclear in A549 cells but translocates to mitochondria in A549/DDP cells. Functional assays demonstrated that H19 silencing in resistant cells attenuated chemoresistance, suppressed proliferation, migration, invasion, and colony formation in vitro, and delayed tumor growth in vivo. H19 knockdown impaired mitophagy and promoted apoptosis, mirroring autophagy inhibition and restoring DDP sensitivity. In contrast, H19 overexpression in A549 cells did not significantly alter mitophagy or cellular behavior. Furthermore, H19 silencing induced its relocalization from mitochondria back to the nucleus in resistant cells, while overexpression did not affect its nuclear localization. These findings establish that H19 translocation to mitochondria promotes DDP resistance, and its downregulation reverses this process by inhibiting mitophagy and resensitizing cells to DDP. As a nucleus-encoded mitochondria-associated lncRNA (ntmtlncRNA), H19 mediates intercompartmental communication, highlighting its potential as a therapeutic target for overcoming DDP resistance in LUAD.