Hepatocellular　carcinoma　(HCC)　poses　a　significant　threat　due　to　its　highly　aggressive　and　high　recurrence　characteristics,　necessitating　urgent　advances　in　diagnostic　and　therapeutic　approaches.　Long　non-coding　RNAs　exert　vital　roles　in　HCC　tumorigenesis,　however　the　mechanisms　of　their　expression　regulation　and　functions　are　not　fully　elucidated　yet.　Herein,　we　identify　that　a　novel　tumor　suppressor　‘lnc-PIK3R1’　was　significantly　downregulated　in　HCC　tissues,　which　was　correlated　with　poor　prognosis.　Functionally,　lnc-PIK3R1　played　tumor　suppressor　roles　to　inhibit　the　proliferation　and　mobility　of　HCC　cells,　and　to　impede　the　distant　implantation　of　xenograft　in　mice.　Mechanistic　studies　revealed　that　lnc-PIK3R1　interacted　with　miR-1286　and　alleviated　the　repression　on　GSK3B　by　miR-1286.　Notably,　pharmacological　inhibition　of　GSK3β　compromised　the　tumor　suppression　effect　by　lnc-PIK3R1,　confirming　their　functional　relevance.　Moreover,　we　identified　that　oncogenic　YY1　acts　as　a　specific　transcriptional　repressor　to　downregulate　the　expression　of　lnc-PIK3R1　in　HCC.　In　summary,　this　study　highlights　the　tumor-suppressive　effect　of　lnc-PIK3R1,　and　provides　new　insights　into　the　regulation　of　GSK3β　expression　in　HCC,　which　would　benefit　the　development　of　innovative　intervention　strategies　for　HCC.　©　2024　Elsevier　B.V.